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ACS Infect Dis. 2015 Feb 13;1(2):98-109. Epub 2014 Dec 15.

A Potent Anti-influenza Compound Blocks Fusion through Stabilization of the Prefusion Conformation of the Hemagglutinin Protein.

Author information

1
Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
2
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute , 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
3
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

Abstract

An ultrahigh-throughput screen was performed to identify novel small molecule inhibitors of influenza virus replication. The screen employed a recombinant influenza A/WSN/33 virus expressing Renilla luciferase and yielded a hit rate of 0.5%, of which the vast majority showed little cytotoxicity at the inhibitory concentration. One of the top hits from this screen, designated S20, inhibits HA-mediated membrane fusion. S20 shows potent antiviral activity (IC50 = 80 nM) and low toxicity (CC50 = 40 μM), yielding a selectivity index of 500 and functionality against all of the group 1 influenza A viruses tested in this study, including the pandemic H1N1 and avian H5N1 viruses. Mechanism of action studies proved a direct S20-HA interaction and showed that S20 inhibits fusion by stabilizing the prefusion conformation of HA. In silico docking studies were performed, and the predicted binding site in HA2 corresponds with the area where resistance mutations occurred and correlates with the known role of this region in fusion. This high-throughput screen has yielded many promising new lead compounds, including S20, which will potentially shed light on the molecular mechanisms of viral infection and serve as research tools or be developed for clinical use as antivirals.

KEYWORDS:

antiviral; docking; fusion; hemagglutinin; influenza; screen

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