Optimization and Structure–Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides

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 encourage further preclinical development of phosphinic pseudotripeptides
as regulators of adaptive immune responses.