1. Optimization and Structure-Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides
- Author
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Dimitris Georgiadis, Ioanna Petropoulou, Paraskevi Kokkala, Efstratios Stratikos, François-Xavier Mauvais, Athanasios Papakyriakou, Anastasia Mpakali, Sofia Kavvalou, Peter van Endert, Theodora-Markisia Fonsou, Mirto Papathanasopoulou, Stefanos Agrotis, and Ira Daskalaki
- Subjects
0301 basic medicine ,Models, Molecular ,Subfamily ,Stereochemistry ,Phosphines ,01 natural sciences ,Aminopeptidase ,Aminopeptidases ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,Immune system ,Drug Discovery ,Animals ,Humans ,Cystinyl Aminopeptidase ,Antigenic peptide ,chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Dendritic Cells ,Orders of magnitude (mass) ,0104 chemical sciences ,Mice, Inbred C57BL ,030104 developmental biology ,Enzyme ,Biochemistry ,Drug Design ,Molecular Medicine ,Selectivity ,Peptides ,Oxytocinase - Abstract
The oxytocinase subfamily of M1 aminopeptidases, consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides can constitute potent inhibitors of this group of enzymes. In this study, we used synthetic methodologies able to furnish a series of stereochemically defined phosphinic pseudotripeptides and demonstrate that side chains at P1′ and P2′ positions are critical determinants in driving potency and selectivity. We identified low nanomolar inhibitors of ERAP2 and IRAP that display selectivity of more than 2 and 3 orders of magnitude, respectively. Cellular analysis demonstrated that one of the compounds that is a selective IRAP inhibitor can reduce IRAP-dependent but not ERAP1-dependent cross-presentation by dendritic cells with nanomolar efficacy. Our results encour...
- Published
- 2016