Identification of a broad-spectrum inhibitor of viral RNA synthesis: validation of a prototype virus-based approach

Chem Biol. 2013 Mar 21;20(3):424-33. doi: 10.1016/j.chembiol.2013.02.011.

Abstract

There are no approved therapeutics for the most deadly nonsegmented negative-strand (NNS) RNA viruses, including Ebola (EBOV). To identify chemical scaffolds for the development of broad-spectrum antivirals, we undertook a prototype-based lead identification screen. Using the prototype NNS virus, vesicular stomatitis virus (VSV), multiple inhibitory compounds were identified. Three compounds were investigated for broad-spectrum activity and inhibited EBOV infection. The most potent, CMLDBU3402, was selected for further study. CMLDBU3402 did not show significant activity against segmented negative-strand RNA viruses, suggesting proscribed broad-spectrum activity. Mechanistic analysis indicated that CMLDBU3402 blocked VSV viral RNA synthesis and inhibited EBOV RNA transcription, demonstrating a consistent mechanism of action against genetically distinct viruses. The identification of this chemical backbone as a broad-spectrum inhibitor of viral RNA synthesis offers significant potential for the development of new therapies for highly pathogenic viruses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Validation Study

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Drug Evaluation, Preclinical
  • Ebolavirus / drug effects*
  • Ebolavirus / genetics*
  • Ebolavirus / growth & development
  • Ebolavirus / physiology
  • Gene Expression Regulation, Viral / drug effects
  • Humans
  • RNA, Viral / biosynthesis*
  • Transcription, Genetic / drug effects
  • Vesiculovirus / drug effects*
  • Vesiculovirus / genetics*
  • Vesiculovirus / growth & development
  • Vesiculovirus / physiology
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • RNA, Viral