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

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.

DOI: 10.1016/j.chembiol.2013.02.011

Cite this paper

@article{Filone2013IdentificationOA, title={Identification of a broad-spectrum inhibitor of viral RNA synthesis: validation of a prototype virus-based approach.}, author={Claire Marie Filone and Erin N Hodges and Brian J. Honeyman and G Guy Bushkin and Karla Boyd and Andrew M. Platt and Feng Ni and Kyle Strom and Lisa E. Hensley and John Snyder and John H. Connor}, journal={Chemistry & biology}, year={2013}, volume={20 3}, pages={424-33} }