Exploration of zinc-binding groups for the design of inhibitors for the oxytocinase subfamily of M1 aminopeptidases |
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| Institution: | 1. National Centre for Scientific Research “Demokritos”, Agia Paraskevi 15310, Greece;2. Center for Magnetic Resonance, University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, FI, Italy;1. Department of Occupational Health and Safety Engineering, School of Health, Alborz University of Medical Sciences, Karaj, Iran;2. Research Center for Health, Safety and Environment, Alborz University of Medical Sciences, Karaj, Iran;3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran;4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran;1. Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria, Australia;2. Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria, Australia;3. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia;4. Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, 246 Clayton Road, Clayton, Victoria, Australia;5. Monash Haematology, Monash Health, 246 Clayton Road, Clayton, Victoria, Australia;1. Departamento de Farmacología, Universidad de Valencia, Valencia, Spain;2. CNRS UMR 6014, C.O.B.R.A. & FR 3038, Université de Rouen, INSA de Rouen, 76131 Mont-Saint-Aignan Cedex, France;3. BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 92290 Châtenay-Malabry, France;4. Instituto de Investigación Sanitaria - INCLIVA, Hospital Clínico Universitario de Valencia, Valencia 46010, Spain;5. Institut Pasteur de Lille, Univ. Lille - EGID, CHU Lille, Inserm U1011, F-59000 Lille, France;6. Institut de Recherches Servier, 92150 Suresnes, France;1. Departamento de Biofísica, Universidade Federal de São Paulo, 04044-020 São Paulo, Brazil;2. Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Agia Paraskevi, GR-15341 Athens, Greece;3. Department of Pharmacy, University of Patras, GR-26504 Patras, Greece;4. Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925 Cape Town, South Africa;5. Departamento de Bioquímica, Universidade Federal de São Paulo, 04039-032 São Paulo, Brasil |
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| Abstract: | The oxytocinase subfamily of M1 aminopeptidases consists of three members, ERAP1, ERAP2 and IRAP that play several important biological roles, including key functions in the generation of antigenic peptides that drive human immune responses. They represent emerging targets for pharmacological manipulation of the immune system, albeit lack of selective inhibitors is hampering these efforts. Most of the previously explored small-molecule binders target the active site of the enzymes via strong interactions with the catalytic zinc(II) atom and, while achieving increased potency, they suffer in selectivity. Continuing our earlier efforts on weaker zinc(II) binding groups (ZBG), like the 3,4-diaminobenzoic acid derivatives (DABA), we herein synthesized and biochemically evaluated analogues of nine potentially weak ZBGs, based on differential substitutions of functionalized pyridinone- and pyridinethione-scaffolds, nicotinic-, isonicotinic-, aminobenzoic- and hydrazinobenzoic-acids. Crystallographic analysis of two analogues in complex with a metalloprotease (MMP-12) revealed unexpected binding topologies, consistent with the observed affinities. Our results suggest that the potency of the compounds as inhibitors of ERAP1, ERAP2 and IRAP is primarily driven by the occupation of active-site specificity pockets and their proper orientation within the enzymes. |
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