[Suppression of hepatitis C virus (HCV) replication with serine palmitoyltransferase inhibitor].
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 chimeric mice. SPT inhibitor led to rapid decline in serum HCV-RNA of about 1-2 log within 8 days. Furthermore, combination therapy of SPT inhibitor and PEG-IFN achieved about 3 log reduction in serum HCV-RNA.
Hirata
Yuichi
Y
Department of Microbiology and Cell biology, The Tokyo metropolitan Institute of Medical Science, Tokyo, Japan.
Sudoh
Masayuki
M
Kohara
Michinori
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D003864:Depression, Chemical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D021962:Membrane Microdomains / Q000821:virology; D051379:Mice; D011485:Protein Binding; D012367:RNA, Viral; D012093:Replicon / Q000187:drug effects; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D013109:Sphingomyelins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D012367:RNA, Viral; D051102:Serine C-Palmitoyltransferase; D013109:Sphingomyelins; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase