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.
Bibliographical noteFunding Information:
We thank Wadsworth Center's Molecular Genetics Core for the DNA sequencing and Cell Culture Facility for the maintenance of BHK-21 and Vero cells. This work was supported partially by federal funds from the National Institute of Allergy and Infectious Disease, National Institutes of Health, under contract NOI-AI-25490, and by NIH grants U01 AI061193 and U54-AI057158 (Northeast Biodefense Center).
- Flavivirus 2K peptide
- Flavivirus replication
- Viral resistance
- West Nile virus