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A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor |
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| Authors: | Gang Zou Francesc Puig-Basagoiti Min Qing Liqiang Chen Krzysztof Felczak Pei-Yong Shi |
| Affiliation: | a Wadsworth Center, New York State Department of Health, USA b State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, China c Graduate School of the Chinese Academy of Sciences, Beijing, China d Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA e Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York, USA |
| Abstract: | Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val → Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound's potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis. |
| Keywords: | Flavivirus replication Antiviral West Nile virus Flavivirus 2K peptide Viral resistance |
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