Suppression of hepatitis C virus (HCV) replication with serine palmitoyltransferase inhibitor

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
Yuichi HirataMichinori Kohara

Abstract

Hepatitis C virus (HCV) persists chronically in most infected patients, eventually causing chronic hepatitis, liver cirrhosis, and in some cases hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves efficacy in many patients, although it does not lead to sufficient achievements in genotype 1b patients. To aid in invention of new anti-HCV reagents, we focused on host factors that contributed to HCV lifecycle. We identified serine palmitoyltransferase inhibitor as an anti-HCV reagent through high-throughput screening using HCV replicon cells. We investigated the mechanism of anti-HCV effect of SPT inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft where replication of HCV occurs. We investigated the influence of SPT inhibitor to lipid rafts by analyzing the detergent-resistant membrane (DRM). The analysis showed that SPT inhibitor moved HCV RNA-dependent RNA polymerase (NS5B) to detergent-soluble fraction from DRM, and Biacore analysis indicated binding of sphingomyelin to NS5B. These results suggest that SPT inhibitor disrupts the interaction between NS5B and sphingomyelin. Moreover, we evaluated the anti-HCV effect of SPT inhibitor in vivo with humanized chime...Continue Reading

References

Jun 26, 2003·Journal of Gastroenterology·Kazuaki InoueMakoto Yoshiba
Aug 28, 2004·The American Journal of Pathology·Chise TatenoKatsutoshi Yoshizato
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Jan 13, 2006·Nature Chemical Biology·Hiroshi SakamotoMasayuki Sudoh
Jun 6, 2006·Biochemical and Biophysical Research Communications·Takuya UmeharaMichinori Kohara
Jan 2, 2007·Biochemical and Biophysical Research Communications·Shin-ichiro NakagawaMichinori Kohara
Mar 30, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kazuaki InoueMichinori Kohara
Oct 30, 2007·World Journal of Gastroenterology : WJG·Anna ParfieniukRobert Flisiak

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Citations

Jun 3, 2011·World Journal of Gastroenterology : WJG·Angela Dolganiuc

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