Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin).
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.
F. Hoffmann-La Roche, Discovery Technologies, 4070 Basel, Switzerland.
Andreas
A
Kuglstatter
Francis
F
Mueller
Eric
E
Kusznir
Bernard
B
Gsell
Martine
M
Stihle
Ralf
R
Thoma
Joerg
J
Benz
Launa
L
Aspeslet
Derrick
D
Freitag
Michael
M
Hennig
D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000737:chemistry* / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000378:metabolism; D007536:Isomerism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D007166:Immunosuppressive Agents; C484071:voclosporin; D016572:Cyclosporine; D021984:Cyclophilin A
J Mol Biol. 1994 Dec 9;244(4):385-409
7990129
Anal Biochem. 2004 Oct 15;333(2):280-8
15450803
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
Transplant Proc. 2004 Mar;36(2 Suppl):125S-129S
15041321
J Am Acad Dermatol. 2006 Mar;54(3):472-8
16488299
Prog Biophys Mol Biol. 1997;67(2-3):155-81
9446934
Mol Interv. 2004 Apr;4(2):97-107
15087483
J Mol Biol. 1998 Oct 23;283(2):435-49
9769216
Structure. 1994 Jan 15;2(1):33-44
8075981
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13522-6
12357034
Transpl Int. 2005 May;17(12):767-71
15827754
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5
20057045
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12037-42
12218175
J Mol Biol. 1993 Dec 20;234(4):1119-30
8263916
Transplantation. 2004 Sep 15;78(5):681-5
15371668
Drug News Perspect. 2003 Jun;16(5):277-82
12942158
Methods Enzymol. 1997;276:307-26
27754618
Anal Biochem. 1983 Jul 15;132(2):353-61
6625170
Biochemistry. 2010 Jun 8;49(22):4679-86
20423153
Curr Opin Investig Drugs. 2004 May;5(5):542-50
15202729
Transplant Proc. 2001 Feb-Mar;33(1-2):1048-51
11267185
Br J Dermatol. 1997 Apr;136(4):531-5
9155953
Semin Cutan Med Surg. 2003 Sep;22(3):187-95
14649586
Acta Crystallogr D Biol Crystallogr. 1997 Jul 1;53(Pt 4):448-55
15299911
J Rheumatol. 2002 Aug;29(8):1646-52
12180723
Cell. 1994 Nov 4;79(3):437-47
7525078
Semin Nephrol. 2003 Sep;23(5):465-76
13680536
Nature. 1993 Jan 7;361(6407):91-4
8421501
Methods Enzymol. 1997;278:221-57
9170316