Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home
  • Log in
  • My Cart

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
Inaugural Article

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

Rameshwar U. Kadam and Ian A. Wilson
  1. aDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037;
  2. bThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037

See allHide authors and affiliations

PNAS January 10, 2017 114 (2) 206-214; first published December 21, 2016; https://doi.org/10.1073/pnas.1617020114
Rameshwar U. Kadam
aDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ian A. Wilson
aDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037;
bThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: wilson@scripps.edu
  1. Contributed by Ian A. Wilson, November 26, 2016 (sent for review October 18, 2016; reviewed by Robert M. Stroud and Jonathan W. Yewdell)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

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.

  • influenza virus
  • hemagglutinin
  • X-ray crystallography
  • Arbidol
  • fusion inhibitor

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.

View Full Text
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Structure of Arbidol with influenza hemagglutinin
Rameshwar U. Kadam, Ian A. Wilson
Proceedings of the National Academy of Sciences Jan 2017, 114 (2) 206-214; DOI: 10.1073/pnas.1617020114

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Structure of Arbidol with influenza hemagglutinin
Rameshwar U. Kadam, Ian A. Wilson
Proceedings of the National Academy of Sciences Jan 2017, 114 (2) 206-214; DOI: 10.1073/pnas.1617020114
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley

Article Classifications

  • Biological Sciences
  • Microbiology

See related content:

  • Profile of Ian A. Wilson
    - Apr 24, 2017
Proceedings of the National Academy of Sciences: 114 (2)
Table of Contents

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Water from a faucet fills a glass.
News Feature: How “forever chemicals” might impair the immune system
Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
Image credit: Shutterstock/Dmitry Naumov.
Reflection of clouds in the still waters of Mono Lake in California.
Inner Workings: Making headway with the mysteries of life’s origins
Recent experiments and simulations are starting to answer some fundamental questions about how life came to be.
Image credit: Shutterstock/Radoslaw Lecyk.
Cave in coastal Kenya with tree growing in the middle.
Journal Club: Small, sharp blades mark shift from Middle to Later Stone Age in coastal Kenya
Archaeologists have long tried to define the transition between the two time periods.
Image credit: Ceri Shipton.
Illustration of groups of people chatting
Exploring the length of human conversations
Adam Mastroianni and Daniel Gilbert explore why conversations almost never end when people want them to.
Listen
Past PodcastsSubscribe
Panda bear hanging in a tree
How horse manure helps giant pandas tolerate cold
A study finds that giant pandas roll in horse manure to increase their cold tolerance.
Image credit: Fuwen Wei.

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Subscribers
  • Librarians
  • Press
  • Cozzarelli Prize
  • Site Map
  • PNAS Updates
  • FAQs
  • Accessibility Statement
  • Rights & Permissions
  • About
  • Contact

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490