Research team

Medicinal Chemistry (UAMC)

Expertise

Koen Augustyns (°13/09/1965) obtained his Master and PhD in Pharmaceutical Sciences at the KU Leuven, Belgium in 1988 and 1992 respectively. After postdoctoral stays at the University of Antwerp, Belgium and the University of Tübingen, Germany he was appointed as Professor of Medicinal Chemistry at the University of Antwerp, Belgium in 1997. His research expertise is in the fields of medicinal chemistry, organic chemistry and organic synthesis. His research in medicinal chemistry is mostly focused on the design and development of novel hit and lead compounds with potential therapeutic applications in the fields of cell death, inflammation and infectious diseases. Recently he became also active in the field of activity-based probes and bioorthogonal chemistry and their applications in bioimaging. He is an experienced teacher in medicinal chemistry and has guided numerous master and PhD students and postdoctoral researchers. He coordinated many national and international research collaborations and as Past President of the European Federation for Medicinal Chemistry he has access to a large international network. As Chair of the department of Pharmaceutical Sciences and Dean of the Faculty of Pharmaceutical, Biomedical and Veterinary Sciences he is experienced in management of people, research and education.

Blocking ischemia reperfusion injury during dynamic preservation of organ grafts using lead ferroptosis inhibitors. 01/10/2021 - 30/09/2024

Abstract

The success of transplantation is hampered by a shortage in suitable organ grafts and the adverse effects of ischemia reperfusion injury (IRI). Inflammation and cell death in the transplanted organ, caused by the activation of the innate immune system as part of the IRI process, leads to primary graft dysfunction (PGD). Transplant recipients that suffer from severe PGD have an increased risk for early and late morbidity and mortality. The organ perfusion strategy was developed to increase the number of available grafts. During the ex situ phase between organ retrieval and transplantation, machine perfusion offers a unique window of opportunity for organ graft modulation to target IRI due to ferroptosis. Ferroptosis is an iron-dependent type of cell death in which oxidative stress initiates excessive lipid peroxidation of cellular membranes leading to cell death. Our in-house developed and patented third generation ferroptosis inhibitors show superior protection in preclinical models of organ injury and are therefore good drug candidates to block injury during transplantation. In this project, we will firstly verify the efficacy of the lead ferroptosis inhibitor in protecting against ferroptosis using genetic organ injury models along experimental IRI or transplantation models in rodents. We will focus on liver, kidney and lungs as vital organs. Secondly, we will analyse the efficacy of adding our lead ferroptosis inhibitor to perfusate during normothermic machine perfusion preceding ex situ reperfusion in pigs. In parallel, we will evaluate the potential of ferroptosis inhibitors to recondition human organ grafts. This research plan is a first step to implement ferroptosis inhibitory strategies in the clinical practice of transplantation, which is a stepping-stone for building a spin-off case in ferroptosis therapeutics.

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Design, synthesis and biological evaluation of novel ferroptosis and necroptosis inhibitors. 01/10/2021 - 30/09/2022

Abstract

Different types of cells deaths play a key role in the pathogenesis of many different diseases such as neurodegenerative disorders, multiorgan injury and cancer. In addition to the well-known apoptosis, novel forms of regulated necrosis have been discovered. Particularly, ferroptosis and necroptosis have emerged as new types of non-apoptotic form of cell death of which ferroptosis is involved in reactive oxygen species (ROS) formation. ROS accumulation promotes damage in different organs and tissues, and could potentially start the release of pro-inflammatory cytokines leading to inflammation and cell membrane disruption. The aim of the project is twofold: 1) the design and synthesis of novel radical trapping agents (RTAs) to hinder the accumulation of lipid hydroperoxides linked with ferroptosis and 2) the design and synthesis of novel receptor interacting serine/threonine kinase 1 (RIPK1) inhibitors to prevent necroptosis. Ferroptosis project: recently, in the MedChem group at the university of Antwerp (UAMC), two novel compounds, namely UAMC-0003203 and UAMC-0003206 have been published and patented as new RTAs able to block the lipid hydroperoxide formation. With higher potency, stability and solubility compared to the well-known benchmark compound Ferrostatin 1, the novel lead compounds can have a therapeutic potential in relevant ferroptosis-driven disease models. A novel library of ferroptosis inhibitors has been successfully synthetized aiming to improve potency, selectivity and ADME properties of the reference compounds. A new ferroptosis in vitro model will be developed in collaboration with prof. Dr. Tom Vanden Berghe to test the library of ferroptosis inhibitors. Necroptosis project: in the necroptosis pathway RIPK1 plays a pivotal role. RIPK1 is a key mediator of inflammation, which is considered the core-mechanism of many pathologies. Thus, RIPK1 is considered a an emerging kinase target in the field of regulated necrosis. A library of Tozasertib analogues, able to selectively inhibit RIPK1, has been synthetized by UAMC. UAMC-0003063 and UAMC-0003064 are the most potent compounds of the library and the improvement of their potency, selectivity and ADME profile was the initial idea of the project. Recently, it was discovered that the GlaxoSmithKline compound GSK2656157, known as a Protein kinase R (PKR)-like ER kinase (PERK) inhibitor, was a potent and selective inhibitor for RIPK1. We therefor studied the differences between the two kinase enzymes PERK and RIPK1 and how the molecule interacts with the active binding site. The development of selective inhibitors is a challenge in the family of protein kinases due to their strong similarities in the ATP binding pocket. Particular attention is therefore given to the interaction with the allosteric pocket, also known as selectivity pocket. Based on a published RIPK1 crystal structure it was possible to further investigate the structural differences between PERK and RIPK1. The synthesis of a novel library of more selective RIPK1 analogues is now being finalized. In vitro tests will be performed to assess the potency and the binding affinity of the novel analogues.

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Design, Synthesis and Biochemical evaluation of novel serine protease activity-based probes. 01/10/2021 - 30/09/2022

Abstract

Serine proteases are a subgroup of the protease family involved in several physiological processes, including immune response, cell death and tissue healing. The upregulation of these proteases can increase inflammatory cytokines, degradation of extracellular matrix components, activation of PAR2 or MMP-9. We previously obtained an in vivo proof of concept with a multi-target serine protease inhibitor (UAMC-00050) in Dry Eye Disease (DED). Topical application of this compound in the eye of a tear-deficient dry eye rat animal model reduced both tissue damage and inflammatory parameters. Moreover, UAMC-00050 also cause a decrease in visceral hypersensitivity in a rat model of post-inflammatory visceral hypersensitivity. Therefore, we hypothesized that serine proteases play an essential role in both DED and Irritable Bowel Syndrome (IBS). The focus of this project is to characterize the proteases involved in DED and IBS. We are using activity-based protein profiling (ABPP), a proteomic technique where chemical probes are used for target identification and drug discovery research. Activity-based probes (ABPs) are small molecules that react covalently with the enzyme active site and facilitate the labelling of target proteins. Up-to-date, a series of 17 new ABPs, analogues from our inhibitor, were synthesized. The challenging synthesis of ABPs required extensive optimization of the synthetic pathways. The phosphonate warhead is crucial to target and bind irreversibly to trypsin-like serine proteases. All ABPs have been biochemically characterized by determining their IC50 in a panel of different serine proteases involved in immune responses. Several potent ABPs have been synthesised and characterized so far. Since ABPs need to bind covalently to the target protein efforts will now be made to describe the most potent probes' kinetic profile by progress curve assays. In addition jump dilution experiments will be performed to discriminate between inhibition mechanisms. In a last stage, ABPs that are potent against the serine proteases of interest and that undergo an irreversible inhibition mechanism will be used to label and identify upregulated proteases in biological samples of DED and IBS patients. Mass spectrometry and gel electrophoresis will be used to detect the ABPs. Identifying the upregulated proteases will allow the design and synthesis of more selective and potent compounds to treat DED and IBS.

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Exploring a novel class of autophagy-inducing small molecules: chemical/biological investigation, target identification and validation in a mouse model of atherosclerosis. 01/11/2020 - 31/10/2023

Abstract

Autophagy is a normal physiological process that removes unnecessary or dysfunctional cellular components from the cytoplasm. Defective autophagy is currently emerging as a hallmark feature of many diseases. In this framework, basic research and drug development have a strong need for reliable, druglike autophagy inducers. In response, we recently carried out a phenotypic highthroughput screen on ~11.000 compounds that were preselected based on druglikeness parameters. In total, 36 potent autophagy inducers were identified. They belong to 10 distinct chemical families that previously have not been associated with autophagy induction. After thorough validation, potency and gross mode-of-action studies, 2 chemical families have been prioritized for further investigation. The proposal comprises the thorough investigation of the most promising family. Structure-Activity Relationships will be constructed and the pharmacophore identified. In addition, chemical optimization will be pursued to obtain analogues with further improved potency and a maximally favorable physico-chemical profile. All novel compounds will be thoroughly investigated in cells and the best performing molecule will be evaluated in an in vivo model of atherosclerosis. Finally, biochemical target identification will be approached via an ensemble of affinity-chromatography, phosphoproteomics and a kinase activity assay.

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Improved PET probes for predicting and imaging immunotherapy responses. 01/10/2020 - 30/09/2023

Abstract

Caspases are well known for their role as executioners of apoptosis. However, recent studies have suggested that these lethal enzymes also have important non-canonical roles in the activation and proliferation of T cells. Effective antitumor immune response is based on the ability of T cells to recognize and destroy cancer cells, for which activation of caspase-3 (c-3) is key. Therefore, the assessment of tumor response based upon the activation of c-3 following immunotherapy, may represent a promising strategy for early prediction of therapy outcome. The current set of c-3-targeted positron emission tomography (PET) radiotracers does not provide adequate resolution and signal-to-noise ratio to precisely visualize c- 3 activity during the course of immunotherapy. In addition, monitoring of CAR T-cell trafficking to the tumor site is still not possible in cancer patients. Therefore, the goal of this application is to develop PET radiotracers for selectively imaging c-3 and to investigate their value for prediction and evaluation of responses to immunotherapy. We propose to use novel c-3 specific cell-permeable activity-based probes to visualize dying tumors following immunotherapy, and c-3 specific cleavable metabolic probes for bioorthogonal monitoring of Tcell activation and trafficking to tumor cells. Probes will be evaluated in vitro to assess c-3 affinity and selectivity, and in vivo using cancer xenograft models treated with immunotherapy for response evaluation.

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Springboard for excellence in advanced development of antibacterials (SPRINGBOARD). 01/09/2020 - 31/08/2023

Abstract

The main goal of SPRINGBOARD project is to strengthen research potential of the Latvian Institute of Organic Synthesis (LIOS) through establishing long-lasting and sustainable collaboration network with the leading European research institutions – University of Antwerp, University of Copenhagen, University of Florence and University of Helsinki – in the area of advanced discovery and design of novel antibacterial drugs.

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Synthesis of a small library of a SurA hit compound, 20-40 analogues, 10 mg of each compound, at least 95% purity. 01/07/2020 - 31/12/2021

Abstract

SurA is a chaperone located in the periplasm of Gram-negative bacteria that is responsible for protecting outer membrane proteins from aggregation in the periplasm and facilitating their delivery to the beta-barrel assembly machinery for folding and insertion into the outer membrane. Inhibition of SurA leads to increased sensitivity to antibiotics and reduced pathogenicity. Therefore, SurA inhibitors have the potential to treat infections with gram-negative bacteria.

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Infla-Med: Fundamental and translational research into targets for the treatment of inflammatory diseases. 01/01/2020 - 31/12/2025

Abstract

The Research Consortium of Excellence Infla-Med combines multidisciplinary expertise of eight research groups from two faculties to perform fundamental and translational research on inflammation, including: inflammatory gastrointestinal, cardiovascular, lung and kidney disorders, sepsis and allergies, as well as parasitic diseases, thereby focusing on specific inflammatory cell populations, including monocytes/macrophages, mast cells, basophils and lymphocytes. The approach of the Infla-Med consortium is twofold. Firstly, fundamental studies are performed to unravel the pathophysiological mechanisms underlying inflammatory conditions in order to enable more rational, targeted and effective intervention strategies. Secondly, Infla-Med aims to identify and validate novel therapeutic targets by screening chemical compounds in early drug discovery studies and by using an extensive platform of in vitro assays and in vivo models. The close collaboration with the Antwerp University Hospital (UZA) creates the opportunity to directly translate and clinically validate experimental findings. Thereby, Infla-Med contributes to two Frontline Research Domains of the University of Antwerp: 'Drug Discovery and Development' and 'Infectious Diseases'. Over the past four years, the multidisciplinary collaborations within Infla-Med have proven to be very successful and productive. By integrating the Infla-Med unique expertise on drug development, in vitro assays and clinically relevant animal models (validated with human samples), significant competitive funding has been acquired at European, national and UAntwerp levels with a success rate of more than 45%, which is far above the (inter)national average. Noteworthy, several Infla-Med projects have also made the transition towards valorization, demonstrating that Infla-Med results obtained from both fundamental research and well-designed preclinical studies can successfully be translated into clinical trials.

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Project website

iMI-project - support - RespiriTB and RaspiriNTM 01/01/2020 - 31/12/2023

Abstract

Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus, cause lung diseases resembling TB, mainly in immune-compromised patients or patients suffering from other lung diseases (e.g. cystic fibrosis). The incidence and prevalence of lung diseases caused by NTM are increasing worldwide. Importantly, in the US and Japan, as well as in other areas of the world where TB has declined, NTM disease is already at least three times more prevalent than TB. Treatment of NTM diseases relies on antibiotic combinations, however the drugs active against NTM are rather few and mainly different than those active against TB. These NTM treatments for the most common species (MAC and M. abscessus) are much less active than the current anti-TB regimen is for TB treatment. It is often necessary to administer antibiotic combinations for at least 12-24 months. The long and complex drug regimen that is currently recommended as a treatment against NTM-caused diseases carries the risk of inducing resistance in NTM. Several studies have already shown the existence and emergence of multidrug resistant NTM. The overall objective of RESPIRI-NTM is to find new drug candidates as potential components of a new, more efficient combination drug regimen against NTM that is less prone to resistance and allows shortening of treatment duration for NTM and multidrug-resistant NTM. Such a drug combination will synergistically target the energy metabolism of NTM or complementary targets. To achieve this, we will advance recently discovered inhibitors of the mycobacterial respiratory pathway. In addition, we will perform a novel, phenotypic screen in order to identify novel targets in NTM. Finally, we will also target host-factors that are essential for the intracellular survival of NTM. Together, we present a comprehensive plan to find novel strategies to combat non-tuberculous mycobacteria, shorten treatment time and reduce chances of drug resistance.

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Project website

Innovating STE(A)M in Higher Education with Transdisciplinary Talent Programs. 01/01/2020 - 31/12/2022

Abstract

Innovating STE(A)M in Higher Education with Transdisciplinary Talent Programs (STEAM+) is a large-scale innovative project with a holistic approach, aiming to provide educational policy makers with instruments to prepare new generations for handling the challenges of our time. Europe faces grand challenges, such as climate change and energy transition, which have a STEM subject at their core, but need transversal skills and knowledge from All other subjects (the extra A) to create STEAM solutions. We need to use brains, hearts and hands of all talents to tackle these challenges. The STEAM+ project uses transdisciplinary talent programs as laboratories of innovation in higher education (HE). The project is co-created by a dedicated and qualified team of 18 partners from 9 countries, bringing together educators, policy makers and future employers, united in their aim to provide new generations with future-proof skills. In the project, we run three international STEAM+ Innovation Labs, where students and teachers from 9 countries come together to co-create solutions for grand challenges. The experience from the Labs and a subsequent series of 54 workshops, 27 national policy meetings and an International Policy Meet-up are used to create two main products: 1. An instrument on how to establish transdisciplinary talent programs in HE: The STEAM+ Innovation Lab Implementation Path; 2. An instrument for policy makers at HE, local, regional, national and EU levels to support and recognize (development of) such programs: the STEAM+ Menu for Policy Inspiration. STEAM+ combines three key innovative elements: 1. Applying a holistic approach, starting with grand challenges, using international, transdisciplinary and educational chain perspectives; 2. Using the proven innovative power of transdisciplinary talent programs; 3. Collaborating transnationally with 18 HE and policy partners and 34 enthusiastic associate partners to optimize dissemination of results and impact.

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    Cell death detection platform. 01/01/2020 - 31/12/2021

    Abstract

    We request funding for two basic infrastructure equipment to measure cell death along any other biochemical parameter that is crucial to determine the mode of cell death such as caspase activation, reactive oxygen species, calcium, mitochondrial membrane potential, lysosomal leakage and lipid peroxidation: 1) FLUOstar® Omega plate reader with atmospheric control unit and 2) BD Accuri C6 Plus personal flow cytometer. These two instruments are perfectly complementary, while the Fluostar provides average values measured on cell populations seeded in any plate up to 384-well plates, the Accuri analyzes at the single cell level allowing to detect heterogenous responses. If the transition from Pathophysiology lab (headed by Patrick D'Haese until 2020) to Cell Death and Inflammation research lab (headed by Tom Vanden Berghe from 2020 onwards) is to proceed smoothly, the investment in this basic but crucial equipment to analyze cell death and related biochemical features is highly needed. Investment in the cell death platform at UAntwerp will boost the recently initiated collaborations in the field of cell death research at UAntwerp. Cell death research is highly present but scattered within the Faculties of FBD and GGW, therefore we initiated monthly sessions of the Cell Death Hot Talks (supported by the OEC Infla-Med). These sessions will (i) increase the exchange on ongoing cell death research, (ii) lead to sharing tools and (iii) boost potential collaborations. Along this line of sharing cell death related expertise and tools, there is a high need to setup a platform to measure and type the mode of cell death within the faculties of FBD and GGW. This investment fits well in the long-term strategic plan in which cell death is one of the four research clusters within the Department of Biomedical Sciences. Moreover, the cell death platform could be instrumental as a steppingstone to make cell death an Emerging Frontline Research Domain.

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    Development of new TCO-probes and their evaluation for a novel pre-targeted intracellular PET imaging strategy. 01/11/2019 - 31/10/2023

    Abstract

    Positron emission tomography (PET) imaging of radiolabeled monoclonal antibodies (mAb) is a powerful in vivo research tool with applications in diagnostic as well as in prognostic and therapeutic settings. The molecular precision of antigen-mAb interaction turns radiolabeled mAbs into highly specific radiotracers with a very high affinity. However, the high molecular weight and the long circulation times of mAbs are associated with unsatisfactory target to background ratios, thus requiring the use of long-lived isotopes which yields high radiation burden to the patient. A pretargeting strategy based in biorthogonal chemistry offers a solution to this problem. In this approach, the mAb with biorthogonal tag will be labeled in vivo with a short lived radiotracer through bioorthogonal reaction at the target site. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs internalize upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims to develop a novel pretargeted intracellular PET imaging strategy. We will develop novel cell permeable fluorinated trans-cyclooctene analogues (TCOs) and investigate their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

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    Progress novel assets (one FIH start) for nontubercular mycobacteria that may act synergistically with bedaquiline and cytochrome bc drugs (RespiriNTM). 01/05/2019 - 30/04/2025

    Abstract

    Non-tuberculous mycobacteria, such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus, cause lung diseases resembling TB, mainly in immune-compromised patients or patients suffering from other lung diseases (e.g. cystic fibrosis). The incidence and prevalence of lung diseases caused by NTM are increasing worldwide. Importantly, in the US and Japan, as well as in other areas of the world where TB has declined, NTM disease is already at least three times more prevalent than TB. Treatment of NTM diseases relies on antibiotic combinations, however the drugs active against NTM are rather few and mainly different than those active against TB. These NTM treatments for the most common species (MAC and M. abscessus) are much less active than the current anti-TB regimen is for TB treatment. It is often necessary to administer antibiotic combinations for at least 12-24 months. The long and complex drug regimen that is currently recommended as a treatment against NTM-caused diseases carries the risk of inducing resistance in NTM. Several studies have already shown the existence and emergence of multidrug resistant NTM. The overall objective of RESPIRI-NTM is to find new drug candidates as potential components of a new, more efficient combination drug regimen against NTM that is less prone to resistance and allows shortening of treatment duration for NTM and multidrug-resistant NTM. Such a drug combination will synergistically target the energy metabolism of NTM or complementary targets. To achieve this, we will advance recently discovered inhibitors of the mycobacterial respiratory pathway. In addition, we will perform a novel, phenotypic screen in order to identify novel targets in NTM. Finally, we will also target host-factors that are essential for the intracellular survival of NTM. Together, we present a comprehensive plan to find novel strategies to combat non-tuberculous mycobacteria, shorten treatment time and reduce chances of drug resistance.

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    Research team(s)

    Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors (RespiriTB). 01/05/2019 - 30/04/2025

    Abstract

    Despite recent progress in biomedical research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is still the world's leading infectious disease killer worldwide. Treatment options are limited, and expensive, recommended medicines are not always available in many countries, and patients experience many adverse effects from the drugs. Thus, there is an acute need for the development of a novel combination regimen with an indication for effective, shorter, and safer treatment of all forms of TB. The overall objective of RESPIRI-TB is to find new drug candidates as potential components of a new, more efficient combination drug regimen against TB that is less prone to resistance and allows shortening of treatment duration for TB, and multidrug-resistant TB. Such a drug combination will synergistically target the energy metabolism of Mtb or complementary targets. To achieve this, we will advance recently discovered inhibitors of the Mtb respiratory pathway. In addition, we will target the Mtb specific molecular mechanism that reduces reactive oxygen species in the cell.

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    Integrated Training in Dry Eye Disease Drug Development (IT-DED3). 01/01/2018 - 31/08/2022

    Abstract

    The European network for Integrated Training in Dry Eye Disease Drug Development (IT-DED3) aims to deliver multidisciplinary and entrepreneurial researchers trained to develop new therapies for patients suffering from dry eye diseases (DED). DED is a chronic, multifactorial disease of the ocular surface and is a major and increasing healthcare problem due to its high prevalence and economic burden because of the ageing population and frequent computer/tablet/smartphone usage. New DED drug development and translation from "bench to bedside" is urgently needed and therefore IT-DED3 integrates worldclass expertise in medicinal chemistry, process chemistry, ocular drug delivery and formulation, DED models, imaging, biomarker research and clinical ophthalmology. The scientific novelty is manifold, including new drug targets and compound classes, innovative formulation strategies for ocular drug delivery, and novel optical and molecular biomarkers identified by new imaging techniques and genomic-based systematic screening of a database of DED patients. The consortium of 7 beneficiaries and 10 partners (in total 7 from the non-academic sector) from 8 different European countries will select 12 early stage researchers (ESRs). Each ESR will perform high level scientific research in this stimulating multidisciplinary, international and intersectoral environment. Besides the scientific skills, the Personal Career Development Plan (PCDP) of each ESR will include transferable skills such as data management, project and time management, communication and dissemination, IP and valorisation. Both the research and training programme of IT-DED3 will deliver researchers with an enhanced career perspective and employability, who know how to use their entrepreneurial skills to move drug development projects in DED and other fields to the next technology readiness level.

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    Synthesis of inhibitors and inhibitor-derived imaging probes for prolyl oligopeptidase (PREP) and dipeptidyl-peptidase (DPP9) with potential application in neurodegenerative disease. 01/01/2018 - 31/03/2022

    Abstract

    Prolyl oligopeptidase (PREP) and dipeptidyl-peptidase 9 (DPP9) are two related serine proteases. PREP is mainly expressed in the central nervous system. This proposal will focus on the possibility to inhibit aggregation of alpha-synuclein (alphaSYN) using active-site directed inhibitors of PREP. alphaSYN plays a key role in the pathophysiologies of Parkinson's and related diseases, where aggregates of alphaSYN precipitate as neurotoxic Lewy-bodies. There are currently no PREPinhibitors that are optimized to block alphaSYN aggregation and that have a biological profile that allows drug development. The proposal will therefore deliver optimized PREP inhibitors. In addition, a PREP-targeting imaging probe will be delivered to image (alphaSYN) in the brain. DPP9 has a wider expression in the human body than PREP, and is also present in the human brain. DPP9 is strongly linked to inflammatory processes, also in the context of neuro-inflammation. The latter is present in nearly all neurodegenerative diseases, including in synucleinopathies and Alzheimer's disease. It is also an early marker of disease that is present before symptoms appear. Of note, there are currently no selective DPP9 inhibitors available. Availability of the latter is essential to obtain preclinical validation of DPP9 inhibitors as novel agents that target neurodegeneration. In addition, the project aims to deliver a DPP9-selective probe for use in neurodegenerative disease imaging.

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    Molecular mechanisms of cellular Death and Life decisions in Inflammation, Degeneration and Infection (MODEL-IDE). 01/01/2018 - 31/12/2021

    Abstract

    The research program on Molecular mechanisms of cellular DEath and Life decisions in Inflammation, Degeneration and Infection (MODEL-IDI) aims at performing fundamental research on the biology of cell death modalities, cell survival regulation and their consequences on the onset and/or progression of diseases. The program aims at linking the discoveries obtained in vitro on the molecular regulation of cell death and inflammation to their in vivo physiological relevance by making use of chemical tool compounds and experimental models of diseases, such as diabetes type I & II, hepatotoxicity and liver cancer, atherosclerosis and neurodegenerative diseases.

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    Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds. 01/01/2018 - 31/12/2021

    Abstract

    Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Necrotic cell death is a kind of cell death in which cells release their cellular content in the surrounding tissue, in contrast to apoptotic cell death. We now realize that multiple forms of regulated necrosis exist. A new type of regulated necrosis that is catalysed by iron was recently unravelled and is now referred to as ferroptosis. Several hereditary conditions have been found that perturb body iron homeostasis and promote pathological deposition of the metal resulting in organ damage in liver, heart, pancreas, thyroid and the central nervous system. For this reason, iron chelators have been implemented or proposed as treatments for these diseases. Because iron is an essential metal for the overall functioning of organisms, whole body scavenging of iron is not preferable due to its expected detrimental side effects. In view of the recent experimental findings that inhibitors of ferroptosis (called ferrostatins) can protect against degenerative diseases, we want to unravel the molecular mechanisms involved in ferroptosis in more detail, identify new ferroptosis inhibitors that can be used in vivo, and validate them in cellular assays and mouse models.

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    ADME study of lead ferroptosis inhibitor which blocks organ injury and neurodegeneration in mice. 03/02/2020 - 30/06/2021

    Abstract

    Ferroptosis is an iron-catalyzed form of regulated necrosis, which is shown to be detrimentally involved in several experimental disease models, such as acute kidney/liver injury and neurodegeneration. Glutathione peroxidase 4 (GPX4) is the central enzyme protecting the cell from excessive lipid peroxidation, which is the key execution process in ferroptosis. A high-throughput screening performed by the Stockwell Lab (Columbia University, US) led to the discovery of ferrostatin-1 (Fer1) as a potent in vitro inhibitor of ferroptosis. In vivo however, the molecule suffers from instability. Therefore, we developed ferrostatin-analogues with improved efficacy, solubility and stability. Ongoing research, in the framework of an FWO research project and an FWO-EOS project, illustrates that our patented lead Fer1--analogue UAMC-3203 is superior as compared to the benchmarks in several ferroptosis-driven experimental disease mouse models. The aim of this project is to study aspects of absorption, distribution, metabolism and excretion of the potential lead ferroptosis inhibitor UAMC-3203 in mice and rats. The results of this POC project should deliver an extended ADME-profile, verify its ability to cross the blood-brain-barrier and validate the possibility to administer UAMC-3203 orally. This will increase the valorisation potential of this compound. As the number of potential applications is relatively big, building a spin-off case for evaluation by seasoned investors and business professionals is likely the most suitable valorisation strategy.

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    Validation of the oxadiazolone isostere as a carboxylate replacement in caspase inhibitors: approaches involving Strecker-based synthetic methodology development and on-target strategies. 01/10/2018 - 30/09/2021

    Abstract

    Caspases are intracellular, aspartate selective cysteine proteases. Given their central role in cell death and inflammation, caspases have been studied intensively as drug targets to date. In spite of impressive preclinical results and significant investment in clinical evaluation, no caspase inhibitors have so far been approved as drugs by FDA or EMA. Two important reasons therefore are commonly cited: (1) The large structural homology of caspases that complicates the identification of selective compounds. (2) The limited biopharmaceutical quality of most compounds. Many contain an irreversible covalent warhead function that can potentially induce off-target effects. Most inhibitor families also contain a free carboxylate. Both the ionic character of this group and its potential for toxic metabolite formation, most probably discount critically on the permeability and ADME-Tox properties of inhibitors. Preliminary work at UAMC has identified the oxadiazolone moiety as a useful isosteric replacement for carboxylates in caspase inhibitors. Research in this proposal will validate this finding by introducing an oxadiazolone group in several relevant classes of caspase inhibitors. In addition, synthetic methodology based on the Strecker reaction will be elaborated. The latter will allow efficient access to caspase inhibitors with less reactive warhead types. Finally, drug discovery methodology will be developed that should allow "on-target" synthesis using caspase 1 as a model.

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    Stabilization of atherosclerotic plaques via inhibition of regulated necrosis. 01/10/2018 - 30/09/2020

    Abstract

    Necrosis is a type of cell death characterized by a gain in cell volume, swelling of organelles, rupture of the plasma membrane and subsequent loss of intracellular contents. For a long time, the process has been considered as a merely accidental and uncontrolled form of cell death, but accumulating evidence suggests that it can also occur in a regulated fashion. Necroptosis is the most understood form of regulated necrosis and requires receptor interacting protein (RIP) kinases as key regulators, but also other examples such as ferroptosis are emerging. Morphological studies using transmission electron microscopy indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis and plaque instability through induction of inflammation and enlargement of the necrotic core. Therefore, the following objectives are defined in the present research proposal: (1) Identification of potential beneficial effects of macrophage-specific RIP1 gene deletion on atherosclerosis development, and (2) stabilization of atherosclerotic plaques with potent and selective inhibitors targeting RIP1 kinase activity or ferroptosis. The project may contribute to the development of novel (add-on) therapies for stabilization of atherosclerotic plaques.

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    Development of novel TCO probes for pretargeted intracellular PET imaging. 01/10/2018 - 31/10/2019

    Abstract

    Radiolabeling of monoclonal antibodies (mAbs) is a powerful preclinical and clinical research tool that finds applications in diagnostic as well as in prognostic and therapeutic settings. Positron Emission Tomography (PET) differs from traditional imaging in that probes known as radiotracers carrying a radioisotope are used to visualize, characterize, and quantify biological processes in vivo. However, despite their attractive properties radiolabeled mAbs have a few important shortcomings. One of the most critical ones is their long circulation time in the body associated with low target to non-target ratios, thus requiring the use of long lived isotopes which yields high radiation dose to the patient. A solution for this problem is offered by pretargeting based on bioorthogonal chemistry. This allows in vivo imaging of the target with superior image contrast and reduced radiation doses. An additional challenge is that many mAbs are internalized upon binding to their target on the cell surface, before the pretargeting reaction. To overcome this issue, this project aims at developing a pretargeted intracellular PET imaging strategy. We will develop novel fluorinated trans-cyclooctene analogues (TCOs) and characterize their potential for pretargeted intracellular imaging using an innovative approach of "turn-on" FluoroBOT labeled mAbs. Finally, following optimization of radiochemistry, the 18F-TCO will be used in an in vivo imaging study.

    Researcher(s)

    Research team(s)

    Drug delivery systems and in vivo efficacy of the serine protease inhibitor UAMC-00050 in a preclinical model for irritable bowel syndrome. 01/10/2018 - 30/09/2019

    Abstract

    The serine protease inhibitor UAMC-00050, previously shown efficacious in 2 preclinical IBS models after systemic administration, will be formulated for oral and rectal administration. The drug delivery systems will be tested in the rat IBS model for dose determination, efficacy, time of administration and serum concentrations, a crucial step towards further valorization of the compound.

    Researcher(s)

    Research team(s)

    Comprehensive Liquid Chromatography - Ion Mobility - Quadrupole-Time-of-Flight Mass Spectrometry for innovative metabolomics. 01/05/2018 - 30/04/2021

    Abstract

    The requested infrastructure (comprehensive liquid chromatograph-ion mobility-quadrupole time of flight mass spectrometer LCxLC-IM-QTOFMS) combines several state-of-the-art technologies into one platform which aims at bringing metabolomics research to the next level. As such, the infrastructure will deliver a combined five-dimension separation and detection technology, the first of its kind in Belgium. This instrument will be dedicated to metabolomics research, the science of endogenous metabolites in cells, tissues or organisms. The infrastructure will be able to optimally separate, detect and identify the very broad and complex chemical space of metabolites ranging from very polar (e.g. amino acids) to non-polar (e.g. lipids and hormones) at low nanomolar concentration range. Within UA, there is a growing need to combine the currently scattered efforts in metabolomics, an Emerging Frontline Research Domain in the UA research scene. Research ranges from drug discovery (mode of action and pharmacokinetic profiling), biomarker and toxicity studies to advanced data-analysis and systems biology approaches, but a dedicated metabolomics infrastructure to strengthen these studies is currently missing. As such, the investment in a core facility together with the gathering of nine research groups from five departments and two faculties would centralize the metabolomics research. This will position UA as a key player in the academic metabolomics research in the BeNeLux and worldwide.

    Researcher(s)

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    Development of novel cell death PET imaging probes for early treatment response evaluation 01/10/2017 - 30/09/2020

    Abstract

    Cell death is a fundamental biological process. As different therapies may result in activation or inhibition of cell death, there is a need for imaging techniques that can identify cell death during the course of patient treatment. The development of molecular probes targeting cell death biomarkers are key. Caspase-3 activation and exposure of phosphatidylethanolamine (PE) in the cell membrane are important biomarkers for cell death. Selective in vivo positron emission tomography (PET) imaging of caspase-3 and PE could therefore aid in the assessment of early response to cancer therapy, preventing exposure of patients to needless toxicity. Recently, the use of unnatural amino acids in the caspase-3 recognition sequence and the modification of prime probe regions were described to be efficient strategies to design caspase-3 selective probes. Duramycin is a small peptide that binds to PE with high affinity and selectivity. The aim of the current work is the development of 18F-duramycin and 18F-labeled caspase-3 selective probes for noninvasive PET imaging of cell death. Following optimization of radiochemistry, the probes will be characterized to assess cell death binding and target selectivity, stability and pharmacokinetic behavior. Clinical applicability of the different probes will be evaluated in well characterized cancer xenograft models treated with targeted therapy or immunotherapy and compared to the clinical gold standard 18F-FDG for therapy response evaluation.

    Researcher(s)

    Research team(s)

    TRP channel sensitization as target for treatment of hypersensitivity (TRP-sensation). 01/07/2017 - 30/06/2021

    Abstract

    IBS affects around 18% of the general population. It is one of the most common disorders seen by physicians. However, the IBS market is commercially weak due to the limited understanding of its pathophysiology and the availability of limited treatment options. In fact, IBS is largely seen as a syndrome rather than a disease. By increasing the understanding of the underlying mechanisms of IBS coupled to validation of therapeutic and diagnostic targets, we have the ambition to turn IBS "from a syndrome into a disease". To achieve this, we want to establish an academic knowledge platform and an industrial network in Flanders that is able to tackle the major challenges in the IBS field, to identify and validate novel therapeutic and diagnostic targets and to develop them into novel therapeutic and diagnostic solutions. When available, this network will put Flanders at the forefront of innovation in the emerging IBS field.

    Researcher(s)

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    On-target assembly of druglike small molecules as protease inhibitors: a bottom-up approach using urokinase plasminogen activator (uPA) as a model target. 01/10/2016 - 30/09/2019

    Abstract

    Common to all contemporary drug discovery strategies is that they revolve around iterative cycles of design, synthesis and potency evaluation, each time producing further optimized compounds. This is generally a very time- and cost-consuming process that could be significantly shortened by implementing so-called "on-target" strategies. The latter rely on direct assistance of the drug target, which serves as a physical template that selects useful drug fragments and assembles them into finalized ligands. In this way, synthesis and potency determination, along with aspects of molecular design, are merged into a single, time-efficient experimental step. This project aims to (1) expand the limited range of chemistry types that are currently known to be amenable to on-target approaches, (2) focusing on reactions that deliver "druglike" molecules. (3) In addition, computational models offering insight at the molecular level in on-target reactions will be developed to rationalize and refine the experimental approaches. As the model target for this project has been selected urokinase plasminogen activator (uPA), a daunting but highly promising drug target. The potential to deliver novel druglike, low nanomolar inhibitors of uPA will be used to assess the value of the on-target approaches. Given the status of uPA as a validated drug target, novel inhibitors of this enzyme have significant value for drug discovery.

    Researcher(s)

    Research team(s)

    Validation of the oxadiazolone isostere as a carboxylate replacement in caspase inhibitors: approaches involving Strecker-based synthetic methodology development and on-target strategies. 01/10/2016 - 30/09/2018

    Abstract

    Caspases are intracellular, aspartate selective cysteine proteases. Given their central role in cell death and inflammation, caspases have been studied intensively as drug targets to date. In spite of impressive preclinical results and significant investment in clinical evaluation, no caspase inhibitors have so far been approved as drugs by FDA or EMA. Two important reasons therefore are commonly cited: (1) The large structural homology of caspases that complicates the identification of selective compounds. (2) The limited biopharmaceutical quality of most compounds. Many contain an irreversible covalent warhead function that can potentially induce off-target effects. Most inhibitor families also contain a free carboxylate. Both the ionic character of this group and its potential for toxic metabolite formation, most probably discount critically on the permeability and ADME-Tox properties of inhibitors. Preliminary work at UAMC has identified the oxadiazolone moiety as a useful isosteric replacement for carboxylates in caspase inhibitors. Research in this proposal will validate this finding by introducing an oxadiazolone group in several relevant classes of caspase inhibitors. In addition, synthetic methodology based on the Strecker reaction will be elaborated. The latter will allow efficient access to caspase inhibitors with less reactive warhead types. Finally, drug discovery methodology will be developed that should allow "on-target" synthesis using caspase 1 as a model.

    Researcher(s)

    Research team(s)

    Stabilization of atherosclerotic plaques via inhibition of regulated necrosis. 01/10/2016 - 30/09/2018

    Abstract

    Necrosis is a type of cell death characterized by a gain in cell volume, swelling of organelles, rupture of the plasma membrane and subsequent loss of intracellular contents. For a long time, the process has been considered as a merely accidental and uncontrolled form of cell death, but accumulating evidence suggests that it can also occur in a regulated fashion. Necroptosis is the most understood form of regulated necrosis and requires receptor interacting protein (RIP) kinases as key regulators, but also other examples such as ferroptosis are emerging. Morphological studies using transmission electron microscopy indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis and plaque instability through induction of inflammation and enlargement of the necrotic core. Therefore, the following objectives are defined in the present research proposal: (1) Identification of potential beneficial effects of macrophage-specific RIP1 gene deletion on atherosclerosis development, and (2) stabilization of atherosclerotic plaques with potent and selective inhibitors targeting RIP1 kinase activity or ferroptosis. The project may contribute to the development of novel (add-on) therapies for stabilization of atherosclerotic plaques.

    Researcher(s)

    Research team(s)

    Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis. 01/10/2016 - 30/09/2018

    Abstract

    The main objective of this research proposal is the discovery of novel chemical tool compounds to investigate the phenotype of necroptosis and ferroptosis at a molecular level in more detail. The use of such tool compounds will result in a better understanding of the different pathways of regulated necrosis, and will also demonstrate where therapeutic targeting is possible, ultimately leading to target identification and validation for novel and innovative treatment opportunities in diseases linked with inflammation and necrotic cell death.

    Researcher(s)

    Research team(s)

    Hit-to lead and lead optimization approaches in Mycobacterium tuberculosis drug-discovery. 15/07/2016 - 14/07/2017

    Abstract

    This DOCPRO1-project is intended to supplement the three year fellowship of Olga Balabon, a Marie Curie PhD fellow in the ITN-EID network "OpenMedChem". OpenMedChem project is open innovation collaboration between the laboratory of Medicinal Chemistry at UA and a major industrial Research&Development unit of GlaxoSmithKline (GSK I+D, Tres Cantos, Spain). OpenMedChem focuses on discovery of novel anti-tuberculosis drug candidates. Despite the existence of treatments for tuberculosis (TB), the threat it represents is still a painful reality for the nearly nine million people infected, and the one and a half million that die each year. The disease also represents an escalating threat for global health, with the increasing prevalence of multi-drug resistant (MDR) TB strains, which are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin - and extensively-drug resistant (XDR) TB that are also resistant to three or more of the six classes of second-line drugs. In an unprecedented move in line with the Open Innovation paradigm, GSK shared with the University of Antwerp its anti-mycobacterial High-Throughput-Screening (HTS) campaign results of over 2 million druglike compounds tested against M.tb. Initial research in this project consisted of a bioinformatics compound clustering into families with promising antitubercular properties. The most promising families were selected for further investigation within the project. Fellow Olga Balabon started with investigating chemical space around a class dihydrotriazines, containing a typical dihydrofolate reductase pharmacophore. Scaffold hopping and decoration delivered a substantial set of novel compounds. Nonetheless, cytotoxicity issues and limitations were decisive to abandon this class of molecules. Instead, Olga is currently working on a class of hydantoin antitubercular compounds that have been identified by GSK as inhibitors of the mycobacterial target decaprenyl-phosphoryl-d-ribose oxidase (DprE1). DprE1 is a recently validated promising mycobacterial drug target. The research during the running time of the DOCPRO1-project aims at in-depth SAR investigation of the substitution pattern on the hydantoin-based DprE1 inhibitors. In addition, a series of hydantoin analogues containing a central pyrrolidine ring, will be explored. Finally, hybrid compounds will be synthesized that consist of complementary fragments of the hydantoin-based DprE1 inhibitors and a previously reported very potent inhibitor (TCA1).

    Researcher(s)

    Research team(s)

    Stabilization of atherosclerotic plaques via inhibition of regulated necrosis. 01/10/2015 - 30/09/2016

    Abstract

    Necrosis is a type of cell death characterized by a gain in cell volume, swelling of organelles, rupture of the plasma membrane and subsequent loss of intracellular contents. For a long time, the process has been considered as a merely accidental and uncontrolled form of cell death, but accumulating evidence suggests that it can also occur in a regulated fashion. Necroptosis is the most understood form of regulated necrosis and requires receptor interacting protein (RIP) kinases as key regulators, but also other examples such as ferroptosis are emerging. Morphological studies using transmission electron microscopy indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis and plaque instability through induction of inflammation and enlargement of the necrotic core. Therefore, the following objectives are defined in the present research proposal: (1) Identification of potential beneficial effects of macrophage-specific RIP1 gene deletion on atherosclerosis development, and (2) stabilization of atherosclerotic plaques with potent and selective inhibitors targeting RIP1 kinase activity or ferroptosis. The project may contribute to the development of novel (add-on) therapies for stabilization of atherosclerotic plaques.

    Researcher(s)

    Research team(s)

    Evaluation of the role of phosphodiesterase 7 and 10 in obsessivecompulsive disorders by positron emission tomography. 01/10/2015 - 15/02/2016

    Abstract

    Patients suffering from obsessive-compulsive disorder (OCD) present symptoms as intrusive, unwanted and recurrent thought or images (obsessions) and or repetitive behaviors (compulsions).These symptoms and behaviors become excessive and disturb significantly daily activities and lead to a low quality of life and a high burden for the family of the patient. The use of serotonin reuptake inhibitor is the most efficient strategy of treatment for OCD but 40 to 60% are refractory to this kind of drugs. So there is a need to look for new therapeutic strategies. Phosphodiesterase (PDE) 7 and 10A inhibitors has been recently proposed as potential treatment in OCD. However none study has been perform to prove this hypothesis. In vivo imaging using Positron Emission Tomography (PET) is a powerful tool to monitor the stages of disease, to study human biology, to investigate in vivo the properties of new drugs in clinical trials. This technique is quantitative and very sensitive and it is a non invasive technique which is a major advantage in brain imaging. Radiotracers are investigated to image in vivo biological targets like a receptor, an enzyme or a tumor. The aim of this project is to use PET imaging to determine the role of PDE7 and PDE10A in OCD and also verify if PDE7 and PDE10A inhibitors could be used as treatment.

    Researcher(s)

    Research team(s)

      Medicinal Chemistry-Drug Discovery (ADDN). 01/01/2015 - 31/12/2020

      Abstract

      This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

      Researcher(s)

      Research team(s)

      INFLA-MED - Fundamental research in the pathophysiological processes of inflammatory diseases. 01/01/2015 - 31/12/2019

      Abstract

      The Infla-Med consortium performs fundamental research on the pathophysiological processes of inflammatory diseases (cardiovascular, gastrointestinal, renal and infectious disease) by using a multidisciplinary approach (pathophysiology, pharmacology, biochemistry and medicinal chemistry). The consortium is embedded within the research priorities 'Drug Research' and 'Infectious Diseases' of the University of Antwerp. Recently, the University of Antwerp assigned the Infla-Med consortium as Research Consortium of Excellence.

      Researcher(s)

      Research team(s)

      Synthesis and characterization of molecular imaging probes for fibroblast activation protein (FAP), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase 8 (DPP8), derived from selective inhibitors. 01/01/2015 - 31/12/2018

      Abstract

      This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

      Researcher(s)

      Research team(s)

      Optimization of novel lead compounds for the treatment of African trypanosomiasis using innovative medicinal chemistry and formulation. 01/01/2015 - 31/12/2018

      Abstract

      The main objective of this research project is the lead optimization of the identified triazine series using medicinal chemistry and formulation technologies to increase the in vivo activity against T. brucei by combining enhanced solubility and metabolic stability with enhanced drug delivery.

      Researcher(s)

      Research team(s)

      Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets (INTEGRATE). 01/01/2015 - 31/12/2018

      Abstract

      The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure will be accomplished through a concrete secondment plan, coupled with a series of high-level consortium-wide training events and networking programmes. Our intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.

      Researcher(s)

      Research team(s)

      Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis. 01/10/2014 - 30/09/2016

      Abstract

      The main objective of this research proposal is the discovery of novel chemical tool compounds to investigate the phenotype of necroptosis and ferroptosis at a molecular level in more detail. The use of such tool compounds will result in a better understanding of the different pathways of regulated necrosis, and will also demonstrate where therapeutic targeting is possible, ultimately leading to target identification and validation for novel and innovative treatment opportunities in diseases linked with inflammation and necrotic cell death.

      Researcher(s)

      Research team(s)

      Partial placement of the NMR infrastructure for the structural elucidation of synthetic and natural substances. 19/05/2014 - 31/12/2018

      Abstract

      This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

      Researcher(s)

      Research team(s)

      Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases (PDE4NPD). 01/03/2014 - 28/02/2018

      Abstract

      This project aims to unite global efforts to target the highly druggable class of enzymes called cyclic nucleotide phosphodiesterases (PDEs) in the fight for neglected parasitic diseases (NPD). It will establish a drug discovery platform, PDE4NPD, that combines phenotypic screening with efficient target-centric drug discovery, including target validation, various strategies for compound screening, PDE hit and lead optimization, safety and toxicology assessments and evaluation of anti-parasitic activity.

      Researcher(s)

      Research team(s)

      Creation of a preclinical platform at the UA for testing novel therapeutic approaches against ocular surface diseases. 01/01/2014 - 31/12/2015

      Abstract

      Ocular Surface diseases (OSD) such as dry eye syndrome (DES) show an estimated prevalence between 15 and 29%. The only FDA approved and on subscription dry-eye treatment is cyclosporine 0.05% (Restasis®), but this formulation is not available in the EU. Novel therapies for OSD are therefore needed. The expertise within ADDN fosters a unique opportunity to set up a preclinical platform on OSD leading to an increased collaboration with industrial partners.

      Researcher(s)

      Research team(s)

      Serthera: locking and monitoring of serine protease activity as the technological base for development of new and innovative drug candidates. 01/06/2013 - 31/08/2014

      Abstract

      The overall aim is to build expertise in the domain of inhibitor and probe development with a focus on serine proteases. The academic platform will establish collaborations with academic and industrial partners. The project will lead to the generation of knowledge in the domain.

      Researcher(s)

      Research team(s)

      PET and SPECT imaging of protease activity by activitybased probes. 01/01/2013 - 31/12/2016

      Abstract

      The main objective of this research proposal is the development of a methodology for PET and SPECT imaging of the enzymatic activity of serine and cysteine proteases using a pretargeting approach with specific activity-based probes and bioorthogonal ligation with radiolabels.

      Researcher(s)

      Research team(s)

      Identification, lead optimization and validation of necroptosis inhibitors. 01/01/2013 - 31/12/2016

      Abstract

      In this project we want to identify novel necroptosis inhibitors by performing a compound screen using a biochemical assay and a cellular assay (mouse and human) for TNF-induced necroptosis. In addition, we will also try to synthesize specific RIPK1 and RIPK3 targeting the ATP-binding pocket.

      Researcher(s)

      Research team(s)

      Activity-based probes for PET imaging of protease activity. 01/01/2013 - 31/12/2016

      Abstract

      Proteases are important drug targets and show increasing application as biomarkers for several diseases. Non-invasive imaging of their proteolytic activity status in vivo offers tremendous potential. We will develop activity-based imaging probes targeting proteases with relevance in oncology and inflammation. These probes will be used in a two-step approach in which the pretargeting step is followed by bioorthogonal ligation with a PET label.

      Researcher(s)

      Research team(s)

      Medicinal chemistry open innovation doctorates (OpenMedChem). 01/10/2012 - 30/09/2016

      Abstract

      In this context, neglected diseases research and development is opening important new avenues of collaboration between academia and industry. The scientific focus of this EID project will be on the design and synthesis of novel antituberculosis drugs. The fellows will have unique access to corporate HTS screening hits while being exposed to both industrial and academic med chem strategies and philosophies. These chemical efforts will be supported by the application of advanced new secondary biological assays for compound evaluation. For example, the fellows will be exposed to cutting edge microfluidics techniques to allow for in depth study of the activities of the new compounds and to provide a platform for investigating the gross modes of action of both novel and known antituberculars.

      Researcher(s)

      Research team(s)

      Design, synthesis and evaluation of new potent radioligands for PDE7 imaging and implication of PDE7 in neurological disorders. 01/10/2012 - 30/09/2015

      Abstract

      The main objective of this project is to develop a PET radiotracer for PDE7 imaging. The PDE7 inhibitors will be used as lead compounds. We selected two families of compounds to increase our chances to discover a suitable PDE7 radiotracer. The structure of the compounds will be modified for labelling with 11C. Precursors for radiolabeling and the 'cold' (non radioactive) standard compounds will be synthesized for radiotracer characterization and in vivo evaluation of PDE7 inhibitory potency and selectivity. The compounds showing the best potency (nanomolar IC50) and selectivity for PDE7 inhibition will be selected for radiolabeling. The next step will be the optimization of the radiosynthesis. The goal will be to obtain the products in a high radiochemical yield and in high radiochemical purity (> 95% for animal studies).

      Researcher(s)

      Research team(s)

        Immuno-positron emission tomography as a potential biomarker for diagnosis and treatment in Alzheimer disease. 01/07/2012 - 30/06/2014

        Abstract

        This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.

        Researcher(s)

        Research team(s)

        Development and functional characterization of inhibitors targeting specific inflammatory caspases. 01/01/2012 - 31/12/2015

        Abstract

        The inflammatory caspases (i.e. mouse caspase-1, -11 and -12, and c human caspase-1, 4-, and -5) modulate inflammatory and host defense responses through the secretion of pro-inflammatory cytokines and the induction of pyroptosis, a pro-inflammatory cell death mode that removes infected immune cells and prevents proliferation of microbial pathogens. However, undesired activation of inflammatory caspases is associated with auto-inflammatory disorders in humans. Thus, the availability of specific inhibitors would offer tremendous opportunities for studying the signaling pathways of inflammatory caspases, and for therapeutic intervention. However, the development of inhibitors that can discriminate between different inflammatory caspases is still a major challenge. Here, we propose two complementary approaches to resolve this issue. In a first approach, optimized peptide-based inhibitors of the inflammatory mouse caspases-1, -11 and -12 will be developed based on their protein substrate repertoires identified by positional proteomics. As a second approach, a targeted chemical library based on selected heterocyclic scaffolds will be developed for the identification of non-peptide small molecule inhibitors of the aforementioned caspases. The potency, selectivity and stability of these peptide- and non-peptide inhibitors will be characterized in biochemical assays and in mouse models of inflammatory and infectious diseases.

        Researcher(s)

        Research team(s)

        ChemPro Tools - Development of chemical tools and proteomics methodology for the study fo proteolytic systems. 01/01/2012 - 31/12/2015

        Abstract

        This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

        Researcher(s)

        Research team(s)

        Project website

        Active center assisted selection and assembly: a bottom-up approach to druglike protease inhibitors using urokinase plasminogen activator as a model target. 01/01/2012 - 31/12/2015

        Abstract

        This project aims at developing an innovative, robust and time/cost-effective methodology with general applicability in the field of protease inhibitor research. As such, it projects the production of target compounds with a non-peptidic architecture consisting of a central, rigid scaffold decorated with substituents that are accomodated in the S- and/or S'-pockets of a target protease. The project's approach differs fundamentally from existing methodologies in its systematic investigation and implementation of target-assisted selection and assembly strategies.

        Researcher(s)

        Research team(s)

        Cysteine protease inhibitors for protozoan infections: metacaspases as promising new targets. 01/10/2011 - 31/08/2013

        Abstract

        Metacaspasen (MCAs) are a new family of cystein proteases found in parasitic protozoa and whom form a valuable new drug target in drug research and development. These proteases are possibly involved in cell death, considered vital for the survival of the parasite and are fundamentally different from the orthologous humane caspases. The objective of this doctorates thesis is the development of powerful and selective inhibitors of the MCA2 of Trypanosoma brucei, with high activity in vitro and low cytotoxicity.

        Researcher(s)

        Research team(s)

        Development of uPA probes as tools for imaging and diagnostic applications. 01/05/2011 - 30/04/2013

        Abstract

        The aim of this project is to further develop uPA probes, of which we already showed the efficacy in in vitro studies, to be used in cellular and in vivo. The IP of these innovative probes have recently been submitted to the UA interface for patenting. The first step in the valorisation of the probes is to obtain proof of concept in in vivo disease models. In the subsequent phase these results will permit us to obtain further funding from larger public (Fournier-Majoie, IWT) or private (VC) institutions. Our goal is to proceed with spinning-out this te chnology into a company preferentially within 3 years.

        Researcher(s)

        Research team(s)

        Topically applicable long-lasting glucocorticoid receptor agonists for the treatment of inflammatory skin diseases. 15/04/2011 - 14/04/2012

        Abstract

        This 'proof-of-concept' research is focussed on the development of innovative long-lasting and selective glucocorticoid receptor agonists for the topical treatment of skin inflammation diseases such as atopic dermatitis and psoriasis.

        Researcher(s)

        Research team(s)

        Validation of Urokinase plasminogen activator (uPA) as a therapeutic target and biomarker. 01/01/2011 - 31/12/2014

        Abstract

        In a first work package, the combination with other conventional therapies as well as anti-metastatic effects and the influence on the angiogenic pathway will be studied. A second work package will determine the metabolic stability of the inhibitors and the possible presence of toxic metabolites. A third work package is necessary to provide enough material for the different test systems and will transform the uPA inhibitors to imaging probes. In a fourth work package, the effect of the uPA inhibitors will be evaluated in a primary and a metastatic tumour model. This project will determine whether these selective and potent irreversible inhibitors can be used for the development of a new therapy and/or as a chemical tool for biomarker/bio-imaging research.

        Researcher(s)

        Research team(s)

          Specific blocking of autophagy processess via inhibition of Atg4B? An approach based on drug-like inhibitors and activity-based probes. 01/01/2011 - 31/12/2014

          Abstract

          This proposal aims at developing inhibitors of cysteine protease Atg4B, a prime regulator of autophagy, as innovative tools for selective autophagy blocking. Additionally, inhibitor-derived probe molecules will be prepared, enabling further study of Atg4B's role in cellular physiology and in the initiation and propagation of autophagic processes.

          Researcher(s)

          Research team(s)

          Active center assisted selection and assembly: a bottom-up approach to druglike protease inhibitors using urokinase plasminogen activator as a model target. 01/01/2011 - 31/12/2011

          Abstract

          This project aims at developing an innovative, robust and time/cost-effective methodology with general applicability in the field of protease inhibitor research. As such, it projects the production of target compounds with a non-peptidic architecture consisting of a central, rigid scaffold decorated with substituents that are accomodated in the S- and/or S'-pockets of a target protease. The project's approach differs fundamentally from existing methodologies in its systematic investigation and implementation of target-assisted selection and assembly strategies.

          Researcher(s)

          Research team(s)

          Fibroblast Activation Protein (FAP) and cancer: development of inhibitors for the treatment of malignant disease and their use as biomarkers FAP probes. 01/10/2010 - 30/09/2014

          Abstract

          This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

          Researcher(s)

          Research team(s)

          Development of urokinase-type plasminogen activator (uPA) inhibitors as potential drugs in anti-metastatic cancer therapy. 01/10/2010 - 30/09/2012

          Abstract

          The following 3 goals were put forward at the start of my PhD research. - Development of reversible uPA inhibitors with a similar or increased activity and selectivity compared with irreversible diarylphosphonates - Optimizing the already synthesised diarylphosphonates - Are the uPA inhibitors also useful in other disease models?

          Researcher(s)

          Research team(s)

          Establishing a high tech purification platform for the purification of natural or synthetic active compounds. 22/07/2010 - 31/12/2014

          Abstract

          This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

          Researcher(s)

          Research team(s)

          Combined highly active anti-retroviral microbicides (CHAARM). 01/01/2010 - 30/06/2015

          Abstract

          The main objective of this project is to develop combinations of highly active specifically-targeted microbicides for vaginal and rectal application. We shall investigate the microbicide potential of protease inhibitors and to test them in combination with inhibitors of HIV-1 reverse transcriptase and/or integrase and/or fusion inhibitors.

          Researcher(s)

          Research team(s)

          From protease inhibitors with increased target residence time to activity-based probes: useful tools in different areas of drug discovery. 01/01/2010 - 31/12/2013

          Abstract

          In this research project we aim to develop protease inhibitors that have the characteristics to become useful chemical tools in different areas of drug discovery. These tools will have the potential to be used in target discovery and target validation, hit and lead identification, for the identification of off-targets, as biomarkers and in molecular imaging.

          Researcher(s)

          Research team(s)

          Optimization of the synthesis of diarylphosphonate inhibitors of serin proteases using reaction calorimetry. 01/01/2010 - 31/12/2011

          Abstract

          The synthesis of diaryl phosphonates, inhibitors of serine proteases, will be optimized and scaled up using reaction calorimetry. The reaction variables that allow for a more efficient Birum-Oleksyszyn reaction, will be identified and studied. In addition, general applicability of results will be assessed during the preparation of a library of potential serine protease inhibitors using a broader spectrum of synthetic substrates.

          Researcher(s)

          Research team(s)

          Cysteine protease inhibitors for protozoan infections: metacaspases as promising new targets. 01/10/2009 - 30/09/2011

          Abstract

          Metacaspasen (MCAs) are a new family of cystein proteases found in parasitic protozoa and whom form a valuable new drug target in drug research and development. These proteases are possibly involved in cell death, considered vital for the survival of the parasite and are fundamentally different from the orthologous humane caspases. The objective of this doctorates thesis is the development of powerful and selective inhibitors of the MCA2 of Trypanosoma brucei, with high activity in vitro and low cytotoxicity.

          Researcher(s)

          Research team(s)

          Development of a click chemistry based synthetic methodology for the synthesis of innovative potential lead compounds and/or chemical probes. 01/10/2009 - 30/09/2010

          Abstract

          Several projects in the Laboratory for Medicinal Chemistry rely on click chemistry (1) as an essential aspect of bio-orthogonal derivatisation of proteins under physiological conditions or (2) as an efficient tool for the construction of innovative biologically active compounds. The candidate will apply his expertise in this domain to support and develop these ongoing projects. Additionally, novel approaches to overcome current boundaries in the domain of click chemistry will be investigated.

          Researcher(s)

          Research team(s)

          Synthesis of diamino acid derivatives with a cyclopropane or aziridine skeleton and their application in the synthesis of potential physiologically active alpha,gamma-diaminobutyric acid derivatives. 01/01/2009 - 31/12/2012

          Abstract

          Objectives of the project: - Development and optimization of the stereoselective synthesis of new derivatives of 1,2-diaminocyclopropane-1-carboxylic acid, 2-amino-2-aziridin-2-ylacetic acid and 2-amino-3-aziridin-2-ylpropionic acid. - Development of ring opening reactions of 1,2-diaminocyclopropane-1-carboxylic acid derivatives, 2-amino-2-aziridin-2-ylacetic acid derivatives and 2-amino-3-aziridin-2-ylpropionic acid derivatives towards potentiallyphysiologically active amino acid derivatives among which 2,4-diaminobutyric acid derivatives. - Biological screening of new conformationally constrained diamino acid derivatives and corresponding ring opened compounds.

          Researcher(s)

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          Dipeptidyl peptidases beyond glucose homeostasis: from biochemistry to physiological importance. 01/01/2009 - 31/12/2012

          Abstract

          This project aims to better understand the effects of chronic dipeptidyl peptidase (DPP) inhibition on pre-defined aspects of cardiovascular, renal and bone (patho)physiology. Inhibitors with defined selectivity profiles will be developed as tools. Expression and inhibition of DPP4 and related peptidases will be studied on the molecular level, in cultured cells and in rat models of ischemia/reperfusion injury of heart and kidney.

          Researcher(s)

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          Bacterial virulence as new target for protease inhibitors. 01/01/2009 - 31/12/2012

          Abstract

          The goal of this project is to gain insight in the role and applicability of protease (DPP4) inhibitors in bacterial infections. The proof-of-concept will be obtained in Porphyromonas gingivalis models with the following objectives and work packages: 1. Development of in vitro and in vivo virulence models for P. gingivalis. 2. Evaluation of enzyme inhibitors using purified recombinant P. gingivalis DPP4. 3. Evaluation of DPP/protease inhibitors in bacterial in vitro and in vivo models. 4. SAR and optimisation of the lead compounds. 5. Biochemical characterisation of lead compound-target enzyme interactions.

          Researcher(s)

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          Structure elucidation of synthetic compounds and natural products by NMR and LC-NMR spectroscopy. 19/12/2008 - 18/12/2013

          Abstract

          This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

          Researcher(s)

          Research team(s)

          Design and synthesis of metacaspase inhibitors as potential lead compounds for antiparasitic chemotherapeutics. 01/10/2008 - 30/09/2010

          Abstract

          This research evolves around a cysteïne protease of Trypanosoma brucei, metacaspase (MCA), of which the function is currently still unknown. Metacaspase has already been tested as drug target, but no MCA inhibitors are known at present. The project focuses on a rational design and synthesis of inhibitors in order to establish a structure-activity-relationship. In a next step, optimization of the achieved inhibitors will be examined. Our final goal is to develop chemically stable inhibitors with a high potency and maximal selectivity with respect to human caspases.

          Researcher(s)

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          FWO-Visiting Postdoctoral Fellowship (Mathusamy Venkatraj, Indië) within the framework of the project "Design, synthesis and evaluation of diverse enzyme inhibitors as potential antiparasitic compounds". 01/11/2007 - 31/10/2008

          Abstract

          Researcher(s)

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          Design, synthesis and evaluation of potent and selective inhibitors of prolyl peptidases of clan SC. 01/10/2007 - 30/09/2010

          Abstract

          Due to the unique structure of proline, relatively few peptidases are able to cleave peptide bonds containing proline. Many biologically active peptides contain an evolutionary conserved proline residue as a proteolytic-processing regulatory element, and therefore proline-specific peptidases are expected to be important 'check-point' controls with great potential as targets for drug discovery. Remarkably, in humans, all enzymes specific for cleaving of a Pro-Xaa bond, are found in clan SC. They share a serine nucleophile and a catalytic triad being in the linear order Ser-Asp-His. This project aims at the development of powerful and selective inhibitors for the catalytically active Pro-Xaa peptidases (DPP IV, DPP II, DPP 8, DPP 9, FAP and POP). Inhibitors will be used primarily for the full functional characterization of the different enzymes and, if possible, for their further validation as therapeutic targets. Inhibitors of DPP IV have been shown to be applicable in the treatment of type II diabetes, while for the other proteins, applications in the domains of oncology (FAP), immunology (DPP II) and the influencing of learning processes and memory (POP) have been proposed. For the rational design of inhibitor molecules, three main elements are used: enzymatic mechanism, substrate specificity, and 3D structure (modeling techniques). In the synthesis of inhibitors, combinatorial and parallel synthetic technologies are applied where feasible. Finally, the biochemical evaluation of compounds is carried out in close collaboration with experts in the field.

          Researcher(s)

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          Heterocyclic synthesis in medicinal and supramolecular chemistry. 01/01/2007 - 31/12/2011

          Abstract

          In the frame of a 'Scientific Research Community 'of the 'Fund for Scientific Research Flanders' (FWO-Flanders) research laboratories of KuLeuven, UG, VUB and UA will collaborate on the topics: - New methodologies in heterocyclic chemistry - Medicinal chemistry based on heterocyclic components - Supramolecular chemistry based on heterocyclic skeletons

          Researcher(s)

          Research team(s)

          Design, synthesis and evaluation of diverse enzyme inhibitors as potential antiparasitic compounds. 01/01/2007 - 31/12/2010

          Abstract

          The research application proposes a further extension of our efforts to develop potent and selective inhibitors for the target proteins, with a strong preference for enzymes involved in parasitic diseases as malaria and trypanosomiasis. In addition to the mere development of compounds with high activity and selectivity, we consider the development or the optimisation of synthetic methodologies for their preparation as an equally valid objective, as well as their funrther structural modification in order to obtain products with desirable pharmacokinetic profiles. A second objective is to investigate the selectivity of inhibitors that were reported by our and other groups with respect to related enzymes.

          Researcher(s)

          Research team(s)

          Synthesis and biological evaluation of nucleoside hydrolase inhibitors as trypanocidal compounds. 01/10/2006 - 30/09/2008

          Abstract

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          Research team(s)

          Serine proteases in the development of new antiparasitic compounds. 01/01/2006 - 31/12/2007

          Abstract

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          Research team(s)

          FWO Visiting Postdoctoral Fellowship. (Georgiana SURPATEANU) 01/10/2005 - 30/09/2006

          Abstract

          Researcher(s)

          Research team(s)

          Peptide- and proteïn mimetics: a combinatorial approach via privileged templates. 01/02/2005 - 31/10/2009

          Abstract

          Researcher(s)

          Research team(s)

          Synthesis and biological evaluation of nucleoside hydrolase inhibitors as potential anti-parasitic agents. 01/10/2004 - 30/09/2006

          Abstract

          Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

          Researcher(s)

          • Promotor: Augustyns Koen
          • Co-promotor: Haemers Achiel
          • Fellow: Goeminne Annelies

          Research team(s)

          Development of new antiparasitic lead compounds against malaria, trypanosomiasis en leishmaniasis : a multidisciplinary approach. 01/01/2004 - 31/12/2007

          Abstract

          Parasitic infections such as malaria, trypanosomiasis and leishmaniasis still make a lot of victims every year, especially in developing countries. The aim of this project is to investigate new lead compounds for drugs against these diseases using a multidisciplinary approach: characterisation of new leads from medicinal plants; further investigations of indoloquinoline derivatives, an existing lead; and design of inhibitors of trypanothionsynthetase and prolyloligopeptidase.

          Researcher(s)

          Research team(s)

          Synthesis and biological evaluation of metalloproteinase and urokinase inhibitors as potential inhibitors of angiogenesis and metastasis. 01/10/2003 - 30/09/2005

          Abstract

          Angiogenesis is a fundamental process in reproduction and wound healing. Under these conditions, neovascularisation is tightly regulated. Unregulated angiogenesis is thought to be indispensable for solid tumor growth and metastasis. Hence, the inhibition of angiogenesis is considered to be one of the most promising strategies that might lead to the development of novel antineoplastic therapies. A plethora of angiogenic factors has been identified in the past 20 years. Most of them are not specific angiogenesis inducers. Urokinase-type plasminogen activator and a few members of the matrix metalloproteinase (MMP)family are considered as selective angiogenic factors and excellent targets for drug design. Urokinase is a serine protease. Compounds with diphenyl aminophosponate tripeptide structure are designed as possible inhibitors. These compounds are characterized by a guanidine or amidine as positioning group. A series of compounds will be synthesized and the guanidine-amidine containing aminophosphonic acid structure optimized. MMP's are zinc proteases and most inhibitors contain zinc binding groups such as hydroxamates. We will use the ?-ketophosphonic acid group as potential inhibiting group. The pseudopeptide structure will be derived from well known structures of the hydroxamate group of compounds, emphasizing the selectivity on MMP2 and MMP9, both involved in angiogenesis. Another series of MMP2 and MMP9 inhibitors to be synthesized are cyclopeptides in which different cyclic structures will be introduced.

          Researcher(s)

          Research team(s)

          Design and synthesis of enzym inhibitors of serine proteases, cysteine proteases and C-N ligases with the aid of parallel solid phase synthesis. (FWO Vis.Fel., El-Tantawy El-Sayed Ibrahim) 01/07/2003 - 30/06/2004

          Abstract

          Prolyl oligopeptidase (POP) is an endopeptidase with serine protease activity that cleaves peptides after proline. Recently POP was isolated from infectious Trypanosoma cruzi, the causative agent of Chagas disease. The enzym plays a crucial role in the invasion of the parasites in mammalia cells, and is therefore a good target for the development of new drugs. POP inhibitors are indeed capable of preventing invasion. Furthermore, POP inhibitors developed in our laboratory are able to kill the parasite. In this project a whole series of POP inhibitors will be synthesised. The inhibitory potential of these inhibitors on the enzym will be investigated, as well as their antiparasitic properties in vitro and in vivo.

          Researcher(s)

          Research team(s)

          N-ribohydrolases as activators of prodrugs. 01/03/2003 - 28/02/2007

          Abstract

          The objective is to design inactive non-toxic prodrugs that can be hydrolysed specifically into ribose and a toxic (parasiticidal) product by particular bacterial or parasitic N-ribohydrolases. The choice for bacterial and parasitic N-ribohdrolases, a family of enzymes that has no representatives within mammals as generic prodrug activating enzymes opens the way to two different prodrug strategies, leading to different therapeutic applications. The first prodrug strategy consists of killing particular bacteria or parasites by systemic cytotoxic compounds that are selectively activated by the parasite's N-ribohydrolase. By including the hyrolases of the genera Campylobacter, Escherichia, Staphylococcus, Trypanosoma, Plasmodium, Leishmania, Pseudomonas, Mycobacterium, and Toxoplasma, we aim to discover a number of new lead compounds that can be developed and validated for the treatment food poisoning and opportunistic infections and against (neglected) infectious diseases including malaria, tuberculosis, sleeping sickness, Chagas disease, and Leishmaniasis. Our second prodrug strategy is based on delivery techniques and includes the activation of non toxic compounds by exogenous ribohydrolases that are targeted to a particular cell type. In this part of the program, we would like to validate gated Self-Assembling NanoStructures (SONS) filled with ribohydrolases as nanoreactors to activate particular prodrugs `in situ'. To deliver these SONS to particular cells, specific single domain antibodies will be fused to theses nanoparticles by chemical or biochemical means.

          Researcher(s)

          Research team(s)

          Design, synthesis and evaluation of inhibitors of nucleoside hydrolases and validation of these enzymes as targets in antiparasitic drug design. 01/01/2003 - 31/12/2006

          Abstract

          Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

          Researcher(s)

          Research team(s)

          Design, synthesis and evaluation of inhibitors of nucleoside hydrolases and validation of these enzymes as target in anti-parasitic drug design. 01/01/2003 - 31/12/2006

          Abstract

          Nucleoside hydrolasen are important enzymes in the purine 'salvage pathway' of parasites such as plasmodia and trypanosoma. They are not found in mammalia. Inhibitors of these enzymes with iminoribitol and cyclopentenr structure are designed with molecular modelling and prepared. They are tested as inhibitors of nucleoside hydrolases and as antiparasitic agent.

          Researcher(s)

          Research team(s)

          Synthesis and biological evaluation of nucleoside hydrolase inhibitors as potential anti-parasitic agents. 01/10/2002 - 30/09/2004

          Abstract

          Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

          Researcher(s)

          • Promotor: Augustyns Koen
          • Co-promotor: Haemers Achiel
          • Fellow: Goeminne Annelies

          Research team(s)

          Design and synthesis of inhibitors of nucleoside hydrolases as potential drugs for the treatment of parasitic infections 01/09/2002 - 31/08/2003

          Abstract

          Protozoa such as Plasmodia, Leishmania and Trypanosomes are the causative agents of several life-threatening or debilitating human tropical diseases, such as malaria, sleeping sickness, Chagas disease and several forms of leishmaniasis. New drugs for these diseases are urgently needed. This project contains computer-aided design, synthesis and enzymatic evaluation of inhibitors of nucleoside hydrolase, a new antiparasitic target.

          Researcher(s)

          Research team(s)

            Design and development of antiangiogenic therapeutics : a multidisciplinary approach. 01/01/2002 - 31/12/2005

            Abstract

            Angiogenesis or the development of new bloodvessels from existing microvascular tissue is a fundamental aspect of many fysiological and pathological processes. Angiogenesis is of fundamental importance in the growth and metastasis of tumors and in chronic inflammatory diseases. Antiangiogenic therapeutics are therefore of potential use in cancer treatment and arthritis. The design and development of antiangiogenic therapeutics in this project will be done either on a rational way, either with at random control of chemical libraries. The rational approach will be based on the design of inhibitors of matrix metalloproteinases (MMP) or of urokinase type plasminogen activator (uPA). We will use ligand-based drug design based on the structure of known inhibitors and substrates and based on the enzymatic mechanism of the target. Since the 3D structure of the targets is known, we will also use structure-based drug desing. The at random approach will be based on the control of antiangiogenic activity of a library of chemical compounds isolated from nature. Especially certain saponins and dihydrobenzofuran lignans with promising acitvities will be further investigated

            Researcher(s)

            Research team(s)

            Synthesis and biological evaluation of metalloproteinase and urokinase inhibitors as potential inhibitors of angiogenesis and metastasis. 01/10/2001 - 30/09/2003

            Abstract

            Angiogenesis is a fundamental process in reproduction and wound healing. Under these conditions, neovascularisation is tightly regulated. Unregulated angiogenesis is thought to be indispensable for solid tumor growth and metastasis. Hence, the inhibition of angiogenesis is considered to be one of the most promising strategies that might lead to the development of novel antineoplastic therapies. A plethora of angiogenic factors has been identified in the past 20 years. Most of them are not specific angiogenesis inducers. Urokinase-type plasminogen activator and a few members of the matrix metalloproteinase (MMP)family are considered as selective angiogenic factors and excellent targets for drug design. Urokinase is a serine protease. Compounds with diphenyl aminophosponate tripeptide structure are designed as possible inhibitors. These compounds are characterized by a guanidine or amidine as positioning group. A series of compounds will be synthesized and the guanidine-amidine containing aminophosphonic acid structure optimized. MMP's are zinc proteases and most inhibitors contain zinc binding groups such as hydroxamates. We will use the ?-ketophosphonic acid group as potential inhibiting group. The pseudopeptide structure will be derived from well known structures of the hydroxamate group of compounds, emphasizing the selectivity on MMP2 and MMP9, both involved in angiogenesis. Another series of MMP2 and MMP9 inhibitors to be synthesized are cyclopeptides in which different cyclic structures will be introduced.

            Researcher(s)

            Research team(s)

              Synthesis of a resin-bound absorptionmodel for a rapid in vitro evaluation of drug candidates. 01/01/2001 - 31/12/2003

              Abstract

              Recent developments in genomics, high-throughput screening and combinatorial chemistry enormously increased the amount of potential therapeutical targets and potential drugs. Because high-throughput determinations of the pharmacokinetic properties are not available, this may well become the rate-limiting step in drug discovery and development. Moreover, the existing pharmacokinetic research is labour- and time consuming and therefore very costly. During this project we will synthesise a drug absorption model on resins that should allow a high-throuhput screening of drug candidates for their absorption potential.

              Researcher(s)

              Research team(s)

              Synthesis of phosphonylated amino acids and their oligopeptides for the design of new medicines and agrochemicals. 11/12/2000 - 11/12/2003

              Abstract

              Aminophosphonic and aminophosphinic acids and derived peptides or pseudopeptides are analogues of amino carboxylic acids and peptides. Several of these compounds have potential use as therapeutic or agrochemical agent. The following topics will be investigated : Total synthesis of antibiotic phosphonopeptides isolated from Bacillus subtilis and Streptomyces luridus. Synthesis of some analogues and evaluation of their biological properties. Synthesis of phosphonic and phosphinic derivatives of spermidine and incorporation in glutathion-like peptides as potential antileishmanial and antitrypanosomal agents. Synthesis of a library of aminophosphonic acids for use in therapeutic and agrochemical projects.

              Researcher(s)

              Research team(s)

              Bio-affinity resins as absorption model for drug candidates. 01/10/2000 - 30/09/2003

              Abstract

              Recent developments in genomics, high-throughput screening and combinatorial chemistry enormously increased the amount of potential therapeutical targets and potential drugs. Because high-throughput determinations of the pharmacokinetic properties are not available, this may well become the rate-limiting step in drug discovery and development. Moreover, the existing pharmacokinetic research is labour- and time consuming and therefore very costly. During this project we will synthesise a drug absorption model on resins that should allow a high-throuhput screening of drug candidates for their absorption potential.

              Researcher(s)

              Research team(s)

                Design and synthesis of enzyme inhibitors against serine proteases, cysteïne proteases en C-N ligases with parallel solid phase synthesis. 01/01/2000 - 31/12/2003

                Abstract

                Development of enzyme inhibitors is one of the most important topics in drug design and development. New structures will be designed using rational drug design methods and prepared in a parallel solid phase system. Targets are the trypanothione synthetase complex as potentiale trypanocide compounds; dipeptidylpeptidase IV and II inhibitors as potential drugs in immune related diseases and diabetes; prolylendopeptidases as potential drugs in brain disorders

                Researcher(s)

                Research team(s)

                Design and synthesis of enzyme inhibitors against serine proteases, cysteïne proteases en C-N ligases with parallel solid phase synthesis. 01/01/2000 - 31/12/2000

                Abstract

                Development of enzyme inhibitors is one of the most important topics in drug design and development. New structures will be designed using rational drug design methods and prepared in a parallel solid phase system. Targets are the trypanothione synthetase complex as potentiale trypanocide compounds; dipeptidylpeptidase IV and II inhibitors as potential drugs in immune related diseases and diabetes; prolylendopeptidases as potential drugs in brain disorders

                Researcher(s)

                Research team(s)

                  Design and synthesis of specific inhibitors of dipeptidyl peptidase II (DPP II) : an investigation on the importance of DPP II in the metabolism of bioactive peptides. 01/01/1999 - 31/12/2000

                  Abstract

                  Introduction : Enzymes are catalysts of biochemical reactions and are essential elements in the biomedical research. The knowledge of their structure, mechanism and functions gives important information for the study on the biochemical basis of diseases and for the development of new drugs. Our laboratory is very experienced in the research on dipeptidyl peptidase IV (DPP IV). This is a protease that cleaves dipeptides from the N-terminus of unsubstituted peptides, preferentially with Ala or Pro at the penultimate position. DPP IV has an important function in the immune system and is involved in the metabolism of bioactive peptides, such as growth hormone releasing factor (GRF), glucagon-like-peptide-1 (7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP IV inhibitors are therefore therapeutically interesting compounds as immunosuppressives, and for the treatment of non-insulin dependent diabetes mellitus and growth hormone deficiency. This is also confirmed in recent investigations. DPP II closely resembles DPP IV, but is less well investigated. However, it might be more specific for Ala at the penultimate position, and hence more active against the above mentioned peptides. Inhibitors of DPP II are therefore potentially more active and selective drugs. Objective : The objective of this research is to unravel the enzymatic and physiological aspects of DPP II, and to demonstrate the therapeutic importance of DPP II inhibitors. Method : At first we will determine the substrate specificity of both enzymes by means of solid phase synthesis of combinatorial libraries. Dipeptide p-nitroanilides will be used to investigate the P2 and P1 position. The research of the P'-site will be done with internally quenched fluorescent substrates. This information will result in the synthesis of compounds (e.g. dipeptide diphenyl phosphonates) for the specific inhibition of DPP II or DPP IV.

                  Researcher(s)

                  Research team(s)

                    Synthesis of enzyme inhibitors on solid phase with the use of new resin linkere. 01/10/1997 - 31/12/1998

                    Abstract

                    Peptidyl hydroxamates will be synthesised on solid phase. This synthesis implicates the development of a new resin linker. The obtained compounds will be tested as inhibitors of glutathionylspermidine synthetase, an essential enzyme for the biosynthesis of trypanothione.

                    Researcher(s)

                    Research team(s)

                      01/10/1996 - 31/12/1996

                      Abstract

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                      Research team(s)