Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin).
Acta Crystallogr D Biol Crystallogr
; 67(Pt 2): 119-23, 2011 Feb.
Article
en En
| MEDLINE
| ID: mdl-21245533
ABSTRACT
E-ISA247 (voclosporin) is a cyclosporin A analogue that is in late-stage clinical development for the treatment of autoimmune diseases and the prevention of organ graft rejection. The X-ray crystal structures of E-ISA247 and its stereoisomer Z-ISA247 bound to cyclophilin A have been determined and their binding affinities were measured to be 15 and 61â
nM, respectively, by fluorescence spectroscopy. The higher affinity of E-ISA247 can be explained by superior van der Waals contacts between its unique side chain and cyclophilin A. Comparison with the known ternary structure including calcineurin suggests that the higher immunosuppressive efficacy of E-ISA247 relative to cyclosporin A could be a consequence of structural changes in calcineurin induced by the modified E-ISA247 side chain.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ciclosporina
/
Ciclofilina A
/
Inmunosupresores
Límite:
Humans
Idioma:
En
Revista:
Acta Crystallogr D Biol Crystallogr
Año:
2011
Tipo del documento:
Article
País de afiliación:
Suiza