Novel broad spectrum inhibitors targeting the flavivirus methyltransferase

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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition.

Original languageEnglish (US)
Article numbere0130062
JournalPloS one
Volume10
Issue number6
DOIs
StatePublished - Jun 22 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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