Multiple cyclophilins involved in different cellular pathways mediate HCV replication.
Three cyclophilin inhibitors (DEBIO-025, SCY635, and NIM811) are currently in clinical trials for hepatitis C therapy. The mechanism of action of these, however, is not completely understood. There are at least 16 cyclophilins expressed in human cells which are involved in a diverse set of cellular processes. Large-scale siRNA experiments, chemoproteomic assays with cyclophilin binding compounds, and mRNA profiling of HCV replicon containing cells were used to identify the cyclophilins that are instrumental to HCV replication. The previously reported cyclophilin A was confirmed and additional cyclophilin containing pathways were identified. Together, the experiments provide strong evidence that NIM811 reduces viral replication by inhibition of multiple cyclophilins and pathways with protein trafficking as the most strongly and persistently affected pathway.
Gaither
L Alex
LA
Novartis Institutes of Biomedical Research, Cambridge, MA 02139, USA.
Borawski
Jason
J
Anderson
Leah J
LJ
Balabanis
Kara A
KA
Devay
Piroska
P
Joberty
Gerard
G
Rau
Christina
C
Schirle
Markus
M
Bouwmeester
Tewis
T
Mickanin
Craig
C
Zhao
Shanchuan
S
Vickers
Chad
C
Lee
Lac
L
Deng
Gejing
G
Baryza
Jeremy
J
Fujimoto
Roger A
RA
Lin
Kai
K
Compton
Teresa
T
Wiedmann
Brigitte
B
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology; D020869:Gene Expression Profiling; D020868:Gene Silencing; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D020543:Proteome / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D000998:Antiviral Agents; D020543:Proteome; D034741:RNA, Small Interfering; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D021983:Cyclophilins