Identification and Characterization of Novel Broad-Spectrum Inhibitors of the Flavivirus Methyltransferase

Matthew Brecher, Hui Chen, Zhong Li, Nilesh K. Banavali, Susan A. Jones, Jing Zhang, Laura D. Kramer, Hongmin Li

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Flavivirus methyltransferase (MTase) is essential for viral replication. Here we report the identification of small molecules through virtual screening that putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function. Six of these computationally predicted binders were identified to show significant MTase inhibition with low micromolar inhibitory activity. The most active compounds showed broad-spectrum activity against the MTase proteins of other flaviviruses. Two of these compounds also showed low cytotoxicity and high antiviral efficacy in cell-based assays. Competitive binding analyses indicated that the inhibitors performed their inhibitory function through competitive binding to the SAM cofactor binding site of the MTase. The crystal structure of the MTase-inhibitor complex further supports the mode of action and provides routes for their further optimization as flavivirus MTase inhibitors.

Original languageEnglish (US)
Pages (from-to)340-349
Number of pages10
JournalACS Infectious Diseases
Volume1
Issue number8
DOIs
StatePublished - Jan 8 2016
Externally publishedYes

Keywords

  • antiviral development
  • flavivirus NS5
  • methyltransferase
  • RNA cap methylation
  • West Nile virus

ASJC Scopus subject areas

  • Infectious Diseases

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