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.
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Paraskevi
P
Kokkala
National Center for Scientific Research "Demokritos" , GR 15310 Agia Paraskevi, Attikis, Greece.
Anastasia
A
Mpakali
Institut National de la Santé et de la Recherche Médicale, Unité 1151, Université Paris Descartes, Sorbonne Paris Cité, Centre National de la Recherche Scientifique, Unité 8253, 75015 Paris, France.
Francois-Xavier
FX
Mauvais
National Center for Scientific Research "Demokritos" , GR 15310 Agia Paraskevi, Attikis, Greece.
Athanasios
A
Papakyriakou
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Ira
I
Daskalaki
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Ioanna
I
Petropoulou
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Sofia
S
Kavvalou
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Mirto
M
Papathanasopoulou
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Stefanos
S
Agrotis
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Theodora-Markisia
TM
Fonsou
Institut National de la Santé et de la Recherche Médicale, Unité 1151, Université Paris Descartes, Sorbonne Paris Cité, Centre National de la Recherche Scientifique, Unité 8253, 75015 Paris, France.
Peter
P
van Endert
National Center for Scientific Research "Demokritos" , GR 15310 Agia Paraskevi, Attikis, Greece.
Efstratios
E
Stratikos
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Zografou, 15771, Athens, Greece.
Dimitris
D
Georgiadis
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D002460:Cell Line; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015195:Drug Design; D006801:Humans; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010455:Peptides / Q000276:immunology; D010720:Phosphines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010455:Peptides; D010720:Phosphines; D000626:Aminopeptidases; C503944:ERAP2 protein, human; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; C044646:phosphine