Host sphingolipid biosynthesis as a target for hepatitis C virus therapy
| Autor: | Atsunori Ohta, Hideyuki Kato, Hiroshi Sakamoto, Yuko Aoki, Michinori Kohara, Koichi Okamoto, Masahiro Aoki, Mikio Arisawa, Asao Katsume, Takuo Tsukuda, Nobuo Shimma, Masayuki Sudoh |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Protein Conformation
Hepatitis C virus Hepacivirus Viral Nonstructural Proteins Biology Virus Replication medicine.disease_cause Cell Line chemistry.chemical_compound Membrane Microdomains Interferon medicine Humans Citrates Molecular Biology NS5B Lipid raft Sphingolipids Phenylpropionates Serine C-palmitoyltransferase virus diseases Cell Biology Hepatitis C Sphingolipid Virology digestive system diseases NS2-3 protease Viral replication chemistry lipids (amino acids peptides and proteins) Protein Binding medicine.drug |
| Zdroj: | Nature Chemical Biology. 1:333-337 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio742 |
| Popis: | An estimated 170 million individuals worldwide are infected with hepatitis C virus (HCV), a serious cause of chronic liver disease. Current interferon-based therapy for treating HCV infection has an unsatisfactory cure rate, and the development of more efficient drugs is needed. During the early stages of HCV infections, various host genes are differentially regulated, and it is possible that inhibition of host proteins affords a therapeutic strategy for treatment of HCV infection. Using an HCV subgenomic replicon cell culture system, here we have identified, from a secondary fungal metabolite, a lipophilic long-chain base compound, NA255 (1), a previously unknown small-molecule HCV replication inhibitor. NA255 prevents the de novo synthesis of sphingolipids, major lipid raft components, thereby inhibiting serine palmitoyltransferase, and it disrupts the association among HCV nonstructural (NS) viral proteins on the lipid rafts. Furthermore, we found that NS5B protein has a sphingolipid-binding motif in its molecular structure and that the domain was able to directly interact with sphingomyelin. Thus, NA255 is a new anti-HCV replication inhibitor that targets host lipid rafts, suggesting that inhibition of sphingolipid metabolism may provide a new therapeutic strategy for treatment of HCV infection. |
| Databáze: | OpenAIRE |
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