Abstract
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 rate1,2, and the development of more efficient drugs is needed. During the early stages of HCV infections, various host genes are differentially regulated3, 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.
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Acknowledgements
We thank N. Ishii for helpful discussions; I. Kusanagi, M. Yamaguchi, K. Onosato and C. Matsuda for technical assistance; and F. Ford and P. Langman for editorial assistance.
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The authors declare competing financial interests: this study was supported financially by Chugai Pharmaceutical Co., Ltd. H.S., K.O., M.A., H.K., A.K., A.O., T.T., N.S., Y.A., M.A. and M.S. are employees of Chugai Pharmaceutical Co., Ltd.
Supplementary information
Supplementary Fig. 1
Effect of NA255 on host-cell viability and cell cycle progression. (PDF 627 kb)
Supplementary Fig. 2
Inhibition of raft localization of NS5B by SPT inhibitor. (PDF 352 kb)
Supplementary Fig. 3
Binding of NS5B to SM. (PDF 475 kb)
Supplementary Table 1
Suppression of SPT inhibitor–mediated anti-replicon activity by sphinganine. (PDF 42 kb)
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Sakamoto, H., Okamoto, K., Aoki, M. et al. Host sphingolipid biosynthesis as a target for hepatitis C virus therapy. Nat Chem Biol 1, 333–337 (2005). https://doi.org/10.1038/nchembio742
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DOI: https://doi.org/10.1038/nchembio742
