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Contributed by Ian A. Wilson, November 26, 2016 (sent for review October 18, 2016; reviewed by Robert M. Stroud and Jonathan W. Yewdell)
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Significance
Influenza virus is an important human pathogen. The circulating strains of influenza virus are constantly mutating and are acquiring resistance to all approved drugs. Therefore, development of influenza therapeutics against novel targets is urgently required. The hemagglutinin envelope glycoprotein (HA) is a promising target for small-molecule design. However, Arbidol is the only available antiviral drug that targets the HA. The absence of structural information on drug–HA complexes has hindered further therapeutic development efforts against this viral pathogen. Here, we report crystal structures of Arbidol in complex with influenza HAs. This structural information advances our understanding of how small molecules, such as Arbidol, can function as influenza fusion inhibitors and can be used for development of broad-spectrum, small-molecule therapeutics.
Abstract
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. 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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: wilson{at}scripps.edu.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016.
Author contributions: R.U.K. and I.A.W. designed research; R.U.K. performed research; R.U.K. and I.A.W. analyzed data; and R.U.K. and I.A.W. wrote the paper.
Reviewers: R.M.S., University of California, San Francisco; and J.W.Y., National Institute of Allergy and Infectious Diseases, National Institutes of Health.
The authors declare no conflict of interest.
Data deposition: Crystallography, atomic coordinates, and structure factors reported in this paper have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 5T6N and 5T6S).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1617020114/-/DCSupplemental.
Structure of Arbidol with influenza hemagglutinin
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