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

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

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1
Department of Microbiology, School of Medicine, Boston University, Boston, MA 02118, USA.

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.

PMID:
23521799
PMCID:
PMC3712830
DOI:
10.1016/j.chembiol.2013.02.011
[Indexed for MEDLINE]
Free PMC Article
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