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Title: A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin

Abstract

The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N-cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that N-cyclohexyltaurine binds to the heart of the conserved HA RBS. N-cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, N-cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. We conclude these long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance ourmore » knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.« less

Authors:
 [1];  [1]
  1. The Scripps Research Inst., La Jolla, CA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1434752
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 115; Journal Issue: 16; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; influenza virus; drug design; X-ray crystallography; fragment; N-cyclohexyltaurine

Citation Formats

Kadam, Rameshwar U., and Wilson, Ian A. A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin. United States: N. p., 2018. Web. doi:10.1073/pnas.1801999115.
Kadam, Rameshwar U., & Wilson, Ian A. A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin. United States. doi:10.1073/pnas.1801999115.
Kadam, Rameshwar U., and Wilson, Ian A. Mon . "A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin". United States. doi:10.1073/pnas.1801999115. https://www.osti.gov/servlets/purl/1434752.
@article{osti_1434752,
title = {A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin},
author = {Kadam, Rameshwar U. and Wilson, Ian A.},
abstractNote = {The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-moleculeN-cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed thatN-cyclohexyltaurine binds to the heart of the conserved HA RBS.N-cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68,N-cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. We conclude these long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.},
doi = {10.1073/pnas.1801999115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 16,
volume = 115,
place = {United States},
year = {2018},
month = {4}
}

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    Works referencing / citing this record:

    Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus
    journal, January 2019


    Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus
    journal, January 2019