The search for new therapeutics involves two major phases:
- In the preclinical phase, new therapeutic approaches are developed and validated in in vitro and in vivo models of human diseases.
- In the subsequent clinical phase, promising preclinical drug candidates are further optimized and validated in clinical trials.
Preclinical Drug Discovery and Development
Preclinical drug discovery and development is characterized by three consecutive steps:
- target discovery,
- Lead discovery, and
- preclinical drug development.
To guarantee a truly integrated approach from ‘hit’ generation to ‘lead’ optimization, the expertise at the University of Antwerp has been bundled into a preclinical drug discovery platform: the Antwerp Drug Discovery Network (ADDN).
Over the past years, considerable expertise has been developed in enzymological targets, including both reversible and irreversible modifiers of enzymatic activity. Furthermore, the platform has already proven useful in the design and development of several protease inhibitors, which are important targets in different disease areas, such as diabetes, cardiology, oncology, tropical diseases (e.g., malaria, Leishmaniasis) and HIV, but which may be equally important as probe molecules in chemical biology and biomarker research.
Target discovery focuses on the identification of potential targets, which requires detailed knowledge of the molecular mechanisms underlying specific pathologies and/or influencing the action of potential therapeutics. It involves target isolation and purification, in vitro and in vivo assay development and testing of compounds. To this end, several recent advanced techniques are applied at the University of Antwerp, including
- knock-out and transgenic animals,
- gene silencing,
- crystallography and
Concomitant access to human material allows extrapolation and validation of the data obtained in the animal experiments.
Drug discovery involves the design or identification of compounds that are capable of influencing the actions of a target. In this respect, the University of Antwerp not only focuses on the design and synthesis of small molecules, but also performs pharmacological, chemotherapeutical and biochemical evaluation and standardisation of traditional plant medicines to find new ‘lead’ compounds with new chemical structures and/or new mechanisms, and to improve the efficacy and safety of these traditional plant medicines. In both cases, structures are revealed and structure- activity/structure-property relationships are established, using a combination of advanced techniques such as bioassay-guided fractionation, 3D molecular modelling and crystallography. Furthermore, dedicated tools are used to screen both synthetic and natural compound libraries for a range of microbial pathogens and parasites.
Preclinical Drug Development
In this phase, the toxicity and pharmacokinetic behaviour of the preclinical candidates are investigated in depth, using integrated in vitro and in vivo screening and selectivity assessment. In this context, biomarker research has become important, since biomarkers can be used as early indicators of efficacy and/or toxicity, which could accelerate clinical development or identify specific patient populations for which the proposed drug candidate shows the most optimal efficacy.
Bio- imaging, which is another frontline research domain of the University of Antwerp, can be particularly valuable for this type of research. State-of-art in vivo and in vitro imaging techniques, as well as in situ and quantative analysis of the target are employed to perform drug binding, efficacy and mechanism of action.
Additionally, the formulation of the drug candidate is investigated at this stage. Both optimization of the more standard oral dosage forms and dedicated research on new and innovative non-oral dosage forms is performed using a wide range of techniques.
Clinical Drug Discovery and Development
As far as clinical drug discovery and development is concerned, the University of Antwerp is involved in performing clinical trials (stage 1-4), including clinical vaccine trials. Our teams not only deal with the design and evaluation of clinical trials, but are also involved in screening of samples for specific metabolites and/or unwanted by-products of the drug under investigation. Additionally, combined expertise in medicine, epidemiology, biostatistics, sociology and economics allows in-depth investigations of the determinants of health and disease and economic evaluations of health programmes.