A general chemical principle for creating closure-stabilizing integrin inhibitors.
Cell
; 185(19): 3533-3550.e27, 2022 09 15.
Article
en En
| MEDLINE
| ID: mdl-36113427
ABSTRACT
Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbß3 and α4ß1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbß3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4ß1.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Integrina alfa4beta1
Idioma:
En
Revista:
Cell
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos