A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor

Gang Zou, Francesc Puig-Basagoiti, Bo Zhang, Min Qing, Liqiang Chen, Krzysztof W. Pankiewicz, Krzysztof Felczak, Zhiming Yuan, Pei-Yong Shi

Research output: Contribution to journalArticle

68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)242-252
Number of pages11
JournalVirology
Volume384
Issue number1
DOIs
StatePublished - Feb 5 2009
Externally publishedYes

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Keywords

  • Antiviral
  • Flavivirus 2K peptide
  • Flavivirus replication
  • Viral resistance
  • West Nile virus

ASJC Scopus subject areas

  • Virology

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