Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin)

被引：42

作者：

Kuglstatter, Andreas ^{[1
]}

Mueller, Francis ^{[1
]}

Kusznir, Eric ^{[1
]}

Gsell, Bernard ^{[1
]}

Stihle, Martine ^{[1
]}

Thoma, Ralf ^{[1
]}

Benz, Joerg ^{[1
]}

Aspeslet, Launa ^{[2
]}

Freitag, Derrick ^{[2
]}

Hennig, Michael ^{[1
]}

机构：

[1] F Hoffmann La Roche, Discovery Technol, CH-4070 Basel, Switzerland

[2] Isotechn Inc, Edmonton, AB T6E 6W2, Canada

来源：

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY | 2011年 / 67卷

关键词：

voclosporin; cyclophilin A; E-ISA247; Z-ISA247; X-RAY-STRUCTURE; CYCLOSPORINE-A; CALCINEURIN INHIBITOR; MOLECULAR REPLACEMENT; LIGAND INTERACTIONS; CRYSTAL-STRUCTURE; COMPLEX; ISA(TX)247; PSORIASIS; FLUORESCENCE;

D O I：

10.1107/S0907444910051905

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

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 61 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.

引用

页码：119 / 123

页数：5

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