Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Kadam, Rameshwar U.; Wilson, Ian A.

doi:10.1073/pnas.1617020114

Title: Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Journal Article · Wed Dec 21 00:00:00 EST 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1617020114· OSTI ID:1343136

Kadam, Rameshwar U. ^[1]; Wilson, Ian A. ^[1]

The Scripps Research Inst., La Jolla, CA (United States)

The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ~16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. Here, this unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Cancer Inst.; National Inst. of General Medical Science (NIGMS); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515; AC02-06CH11357; Y1-CO-1020; Y1-GM-1104; P41GM103393; R56 AI117675

OSTI ID:: 1343136

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 2; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 230 works

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60 APPLIED LIFE SCIENCES
influenza virus
hemagglutinin
X-ray crystallography
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fusion inhibitor

Title: Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

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