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A potent anti-influenza compound blocks fusion through stabilization of the prefusion conformation of the hemagglutinin protein


White, K M; De Jesus, P; Chen, Z; Abreu Jr, P; Barile, E; Mak, P A; Anderson, P; Nguyen, Q T; Inoue, A; Stertz, S; Koenig, R; Pellecchia, M; Palese, P; Kuhen, K; García-Sastre, A; Chanda, S K; Shaw, M L (2014). A potent anti-influenza compound blocks fusion through stabilization of the prefusion conformation of the hemagglutinin protein. ACS Infectious Diseases, 1:98-109.

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 (IC 50=80 nM) and low toxicity (CC50=40μM), yielding a selectivity index of 500 and functionality against all of the group 1influenza 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.

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 (IC 50=80 nM) and low toxicity (CC50=40μM), yielding a selectivity index of 500 and functionality against all of the group 1influenza 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:15 December 2014
Deposited On:22 Apr 2015 15:33
Last Modified:05 Apr 2016 19:13
Publisher:American Chemical Society (ACS)
ISSN:2373-8227
Funders:National Institutes of Health (NIH) Grants U01 AI1074539, HHSN272200900032C, R21 AI102169, U19 AI106754, U19 AI109946, P01 AI097092, NIAID CEIRS HHSN272201400008C
Publisher DOI:https://doi.org/10.1021/id500022h
Official URL:http://pubs.acs.org/journal/aidcbc
Related URLs:http://pubs.acs.org/doi/pdf/10.1021/id500022h
PubMed ID:25984567

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