In the framework of a large EU-FP7 research project on the development of microbicides for the prevention of HIV/AIDS (CHAARM) we developed a series of novel and highly interesting non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our lead compound (UAMC-01398) is highly potent against wild-type HIV, but also against resistant strains.1-3 Furthermore, it is extremely difficult for the virus to develop resistance against our compound.4 Because of its interesting properties UAMC-01398, formulated in a vaginal gel, was selected by the FP7-consortium as the most promising compound to be tested in pharmacokinetic and RT-SHIV challenge studies in macaques.5, 6 It was shown that our compound offered significant protection against HIV infection. Since the compound also demonstrates interesting oral pharmacokinetic properties, we are currently seeking funding for oral pre-exposure prophylactic studies.
1. Arien, K. K.; Venkatraj, M.; Michiels, J.; Joossens, J.; Vereecken, K.; Van der Veken, P.; Abdellati, S.; Cuylaerts, V.; Crucitti, T.; Heyndrickx, L.; Heeres, J.; Augustyns, K.; Lewi, P. J.; Vanham, G. Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission. J. Antimicrob. Chemother. 2013, 68, 2038-2047.2. Venkatraj, M.; Arien, K. K.; Heeres, J.; Joossens, J.; Messagie, J.; Michiels, J.; Van der Veken, P.; Vanham, G.; Lewi, P. J.; Augustyns, K. Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents. Bioorg. Med. Chem. Lett. 2012, 22, 7174-7178.3. Venkatraj, M.; Arien, K. K.; Heeres, J.; Dirie, B.; Joossens, J.; Van Goethem, S.; Van der Veken, P.; Michiels, J.; Velde, C.; Vanham, G.; Lewi, P. J.; Augustyns, K. Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Bioorg. Med. Chem. 2011, 19, 5924-5934.4. Arien, K. K.; Venkatraj, M.; Michiels, J.; Joossens, J.; Vereecken, K.; Van der Veken, P.; Heeres, J.; De Winter, H.; Heyndrickx, L.; Augustyns, K.; Vanham, G. Resistance and cross-resistance profile of the diaryltriazine NNRTI and candidate microbicide UAMC01398. J. Antimicrob. Chemother. 2016, 71, 1159-1168.5. Grammen, C.; Arien, K. K.; Venkatraj, M.; Joossens, J.; Van der Veken, P.; Heeres, J.; Lewi, P. J.; Haenen, S.; Augustyns, K.; Vanham, G.; Augustijns, P.; Brouwers, J. Development and in vitro evaluation of a vaginal microbicide gel formulation for UAMC01398, a novel diaryltriazine NNRTI against HIV-1. Antiviral Res. 2014, 101, 113-121.6. Grammen, C.; Van den Mooter, G.; Appeltans, B.; Michiels, J.; Crucitti, T.; Arien, K. K.; Augustyns, K.; Augustijns, P.; Brouwers, J. Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398. Int. J. Pharm. 2014, 475, 238-244.
Recently, UAMC started a collaboration with the pharma company GSK to optimize novel lead compounds targeting Mycobacterium tuberculosis.7, 8 This project comprises “open innovation” drug discovery aiming at hit-to-lead optimization and target finding for antimycobacterial hits identified by GSK during a High-Throughput Screening campaign. Four compound families are being studied, which were characterized as ligands of DHFR, Dpr-E1 and methionine aminopeptidase. The target for the fourth family was identified by others as being cytochrome bc1.
7. Pitta, E.; Balabon, O.; Rogacki, M. K.; Gomez, J.; Cunningham, F.; Joosens, J.; Augustyns, K.; van der Veken, P.; Bates, R. Differential characterization using readily accessible NMR experiments of novel N- and O-alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives with antimycobacterial activity. Eur. J. Med. Chem. 2017, 125, 890-901.8. Pitta, E.; Rogacki, M. K.; Balabon, O.; Huss, S.; Cunningham, F.; Lopez-Roman, E. M.; Joossens, J.; Augustyns, K.; Ballell, L.; Bates, R. H.; Van der Veken, P. Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2-Quinolin-4-yloxyacetamides. J. Med. Chem. 2016, 59, 6709-6728
This is a longstanding research line in which we investigated multiple targets.
Parasitic phosphodiesterases: UAMC is part of a large EU-funded consortium that aims to validate phosphodiesterases as targets for parasitic diseases. Currently, we are optimizing the pharmacokinetic properties of a lead compound targeting T. brucei.
Compounds derived from NNRTI’s: We have identified an interesting series of highly potent antitrypansomal compounds that are structurally derived from our NNRTI series.9 Currently, we are optimizing the in vivo pharmacokinetic properties.
Nucleoside hydrolases: These enzymes have an important function in the purine salvage in parasites of the Trypanosomatidae family. We managed to develop nanomolar inhibitors that are furthermore highly selective against the human purine nucleoside phosphorylase.10, 11 One of the compounds showed a particular interesting activity against T. brucei and was further investigated in a mechanism-of-action study12 and in a crystal structure bound to the target.13, 14
Metacaspases: This is a unique family with Arg/Lys substrate specificity that is substantially different from human caspases and that are important for the proliferation of T. brucei. The compounds we developed were potent in vitro, but not promising enough to be investigated further.15
9. Venkatraj, M.; Arien, K. K.; Heeres, J.; Joossens, J.; Dirie, B.; Lyssens, S.; Michiels, J.; Cos, P.; Lewi, P. J.; Vanham, G.; Maes, L.; Van der Veken, P.; Augustyns, K. From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds. Bioorg. Med. Chem. 2014, 22, 5241-5248.10. Berg, M.; Bal, G.; Goeminne, A.; Van der Veken, P.; Versees, W.; Steyaert, J.; Haemers, A.; Augustyns, K. Synthesis of Bicyclic N-Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors. ChemMedChem 2009, 4, 249-260.11. Goeminne, A.; Berg, M.; McNaughton, M.; Bal, G.; Surpateanu, G.; Van der Veken, P.; De Prol, S.; Versees, W.; Steyaert, J.; Haemers, A.; Augustyns, K. N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase. Bioorg. Med. Chem. 2008, 16, 6752-6763.12. Berg, M.; Kohl, L.; Van der Veken, P.; Joossens, J.; Al-Salabi, M. I.; Castagna, V.; Giannese, F.; Cos, P.; Versees, W.; Steyaert, J.; Grellier, P.; Haemers, A.; Degano, M.; Maes, L.; de Koning, H. P.; Augustyns, K. Evaluation of Nucleoside Hydrolase Inhibitors for Treatment of African Trypanosomiasis. Antimicrob. Agents Chemother. 2010, 54, 1900-1908.13. Giannese, F.; Berg, M.; Van der Veken, P.; Castagna, V.; Tornaghi, P.; Augustyns, K.; Degano, M. Structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals and a novel metalorganic inhibitor. Acta Crystallogr. Sect. D-Biol. Crystallogr. 2013, 69, 1553-1566.14. Versees, W.; Goeminne, A.; Berg, M.; Vandemeulebroucke, A.; Haemers, A.; Augustyns, K.; Steyaert, J. Crystal structures of T. vivax nucleoside hydrolase in complex with new potent and specific inhibitors. BBA-Proteins Proteomics 2009, 1794, 953-960.15. Berg, M.; Van der Veken, P.; Joossens, J.; Muthusamy, V.; Breugelmans, M.; Moss, C. X.; Rudolf, J.; Cos, P.; Coombs, G. H.; Maes, L.; Haemers, A.; Mottram, J. C.; Augustyns, K. Design and evaluation of Trypanosoma brucei metacaspase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 2001-2006.
In the framework of a collaboration with Janssen Pharmaceutica we recently developed a novel chemotype with interesting antifungal properties.16
16. De Wit, K.; Augustyns, K.; Meerpoel, L.; Maes, L. Novel antifungal 5,6-dihydro-4H-pyrrolobenzodiazepines substituted with heterocyclic derivatives. WO2012150305 (A1) 2012.
As partner in a EU-ITN project we recently started developing covalent inhibitors for the ClpP protease of gram-negative bacteria. First hit compounds have been discovered.