Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 19, Pages 9107-9123Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01031
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Funding
- Special Account for Research Grants of National and Kapodistrian University of Athens
- European Union (European Social Fund)
- Greek national funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework: Research Funding Program of the General Secretariat for Research and Technology [ERC-14]
- Harry J. Lloyd Charitable trust
- Fondation pour la Recherche Medicale [DEQ20130326539]
- Agence Nationale de Recherche [ANR-14-CE11-0014]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE11-0014] Funding Source: Agence Nationale de la Recherche (ANR)
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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 P-1' and P-2' 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 encourage further preclinical development of phosphinic pseudotripeptides as regulators of adaptive immune responses.
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