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Title: Molecular mechanism of respiratory syncytial virus fusion inhibitors

Abstract

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

Authors:
ORCiD logo [1];  [2];  [2];  [3];  [3];  [4];  [4];  [5];  [5];  [6];  [4];  [7];  [8];  [4];  [1]
  1. Geisel School of Medicine at Dartmouth, Hanover, NH (United States). Dept. of Biochemistry
  2. Janssen Infectious Diseases and Vaccines, Leiden (Netherlands)
  3. The Research Inst. at Nationwide Children's Hospital, Columbus, OH (United States). Center for Vaccines & Immunity
  4. Janssen Infectious Diseases & Vaccines BVBA, Beerse (Belgium). Respiratory Infections Research
  5. Janssen Pharmaceutica NV, Beerse (Belgium). Discovery Sciences
  6. Janssen Infectious Diseases & Vaccines BVBA, Beerse (Belgium). Medicinal Chemistry Dept.
  7. Janssen R&D LLC, Spring House, PA (United States). Computational Chemistry
  8. The Research Inst. at Nationwide Children's Hospital, Columbus, OH (United States). Center for Vaccines & Immunity; The Ohio State Univ., Columbus, OH (United States). College of Medicine. Dept. of Pediatrics
Publication Date:
Research Org.:
Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States); Charles H. Hood Foundation (United States)
Contributing Org.:
The Ohio State Univ., Columbus, OH (United States); Janssen Infectious Diseases and Vaccines, Leiden (Netherlands); The Research Inst. at Nationwide Children's Hospital, Columbus, OH (United States); Janssen Infectious Diseases & Vaccines BVBA, Beerse (Belgium); Janssen Pharmaceutica NV, Beerse (Belgium); Janssen R&D LLC, Spring House, PA (United States)
OSTI Identifier:
1239404
Grant/Contract Number:  
AC02-06CH11357; AI 095684
Resource Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 12; Journal Issue: 2; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Infectious diseases; Mechanism of action; Structure-based drug design; Virology; X-ray crystallography

Citation Formats

Battles, Michael B., Langedijk, Johannes P., Furmanova-Hollenstein, Polina, Chaiwatpongsakorn, Supranee, Costello, Heather M., Kwanten, Leen, Vranckx, Luc, Vink, Paul, Jaensch, Steffen, Jonckers, Tim H. M., Koul, Anil, Arnoult, Eric, Peeples, Mark E., Roymans, Dirk, and McLellan, Jason S. Molecular mechanism of respiratory syncytial virus fusion inhibitors. United States: N. p., 2015. Web. doi:10.1038/nchembio.1982.
Battles, Michael B., Langedijk, Johannes P., Furmanova-Hollenstein, Polina, Chaiwatpongsakorn, Supranee, Costello, Heather M., Kwanten, Leen, Vranckx, Luc, Vink, Paul, Jaensch, Steffen, Jonckers, Tim H. M., Koul, Anil, Arnoult, Eric, Peeples, Mark E., Roymans, Dirk, & McLellan, Jason S. Molecular mechanism of respiratory syncytial virus fusion inhibitors. United States. doi:10.1038/nchembio.1982.
Battles, Michael B., Langedijk, Johannes P., Furmanova-Hollenstein, Polina, Chaiwatpongsakorn, Supranee, Costello, Heather M., Kwanten, Leen, Vranckx, Luc, Vink, Paul, Jaensch, Steffen, Jonckers, Tim H. M., Koul, Anil, Arnoult, Eric, Peeples, Mark E., Roymans, Dirk, and McLellan, Jason S. Mon . "Molecular mechanism of respiratory syncytial virus fusion inhibitors". United States. doi:10.1038/nchembio.1982. https://www.osti.gov/servlets/purl/1239404.
@article{osti_1239404,
title = {Molecular mechanism of respiratory syncytial virus fusion inhibitors},
author = {Battles, Michael B. and Langedijk, Johannes P. and Furmanova-Hollenstein, Polina and Chaiwatpongsakorn, Supranee and Costello, Heather M. and Kwanten, Leen and Vranckx, Luc and Vink, Paul and Jaensch, Steffen and Jonckers, Tim H. M. and Koul, Anil and Arnoult, Eric and Peeples, Mark E. and Roymans, Dirk and McLellan, Jason S.},
abstractNote = {Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.},
doi = {10.1038/nchembio.1982},
journal = {Nature Chemical Biology},
number = 2,
volume = 12,
place = {United States},
year = {2015},
month = {12}
}

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Cited by: 23 works
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    Works referencing / citing this record:

    Iduronic Acid-Containing Glycosaminoglycans on Target Cells Are Required for Efficient Respiratory Syncytial Virus Infection
    journal, June 2000

    • Hallak, Louay K.; Collins, Peter L.; Knudson, Warren
    • Virology, Vol. 271, Issue 2
    • DOI: 10.1006/viro.2000.0293

    Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus
    journal, November 2003


    Characteristics of arbidol-resistant mutants of influenza virus: Implications for the mechanism of anti-influenza action of arbidol
    journal, February 2009


    Structural basis of viral invasion: lessons from paramyxovirus F
    journal, August 2007

    • Lamb, Robert A.; Jardetzky, Theodore S.
    • Current Opinion in Structural Biology, Vol. 17, Issue 4
    • DOI: 10.1016/j.sbi.2007.08.016

    Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120
    journal, November 2008


    Strategic priorities for respiratory syncytial virus (RSV) vaccine development
    journal, April 2013


    Elevated temperature triggers human respiratory syncytial virus F protein six-helix bundle formation
    journal, January 2010


    Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones
    journal, March 1993

    • Bodian, Dale L.; Yamasaki, R. Bryan; Buswell, Richard L.
    • Biochemistry, Vol. 32, Issue 12
    • DOI: 10.1021/bi00063a007

    Structure-Based Identification and Neutralization Mechanism of Tyrosine Sulfate Mimetics That Inhibit HIV-1 Entry
    journal, August 2011

    • Acharya, Priyamvada; Dogo-Isonagie, Cajetan; LaLonde, Judith M.
    • ACS Chemical Biology, Vol. 6, Issue 10
    • DOI: 10.1021/cb200068b

    Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors
    journal, April 2012

    • LaLonde, Judith M.; Kwon, Young Do; Jones, David M.
    • Journal of Medicinal Chemistry, Vol. 55, Issue 9
    • DOI: 10.1021/jm300265j

    Discovery of an Oral Respiratory Syncytial Virus (RSV) Fusion Inhibitor (GS-5806) and Clinical Proof of Concept in a Human RSV Challenge Study
    journal, January 2015

    • Mackman, Richard L.; Sangi, Michael; Sperandio, David
    • Journal of Medicinal Chemistry, Vol. 58, Issue 4
    • DOI: 10.1021/jm5017768

    Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)
    journal, February 2008

    • Bonfanti, Jean-François; Meyer, Christophe; Doublet, Frédéric
    • Journal of Medicinal Chemistry, Vol. 51, Issue 4
    • DOI: 10.1021/jm701284j

    A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry
    journal, August 2014

    • Herschhorn, Alon; Gu, Christopher; Espy, Nicole
    • Nature Chemical Biology, Vol. 10, Issue 10
    • DOI: 10.1038/nchembio.1623

    Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state
    journal, February 2017

    • Rossey, Iebe; Gilman, Morgan S. A.; Kabeche, Stephanie C.
    • Nature Communications, Vol. 8, Issue 1
    • DOI: 10.1038/ncomms14158

    A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism
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    • Krarup, Anders; Truan, Daphné; Furmanova-Hollenstein, Polina
    • Nature Communications, Vol. 6, Issue 1
    • DOI: 10.1038/ncomms9143

    Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor
    journal, August 2017


    Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein
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    Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins
    journal, March 2004

    • Si, Z.; Madani, N.; Cox, J. M.
    • Proceedings of the National Academy of Sciences, Vol. 101, Issue 14
    • DOI: 10.1073/pnas.0307953101

    Targeting a binding pocket within the trimer-of-hairpins: Small-molecule inhibition of viral fusion
    journal, October 2004

    • Cianci, C.; Langley, D. R.; Dischino, D. D.
    • Proceedings of the National Academy of Sciences, Vol. 101, Issue 42
    • DOI: 10.1073/pnas.0406696101

    Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion
    journal, November 2008

    • Russell, R. J.; Kerry, P. S.; Stevens, D. J.
    • Proceedings of the National Academy of Sciences, Vol. 105, Issue 46
    • DOI: 10.1073/pnas.0807142105

    Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein
    journal, December 2009

    • Roymans, D.; De Bondt, H. L.; Arnoult, E.
    • Proceedings of the National Academy of Sciences, Vol. 107, Issue 1
    • DOI: 10.1073/pnas.0910108106

    Architecture of respiratory syncytial virus revealed by electron cryotomography
    journal, June 2013

    • Liljeroos, L.; Krzyzaniak, M. A.; Helenius, A.
    • Proceedings of the National Academy of Sciences, Vol. 110, Issue 27
    • DOI: 10.1073/pnas.1309070110

    Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors
    journal, August 2014

    • Yan, D.; Lee, S.; Thakkar, V. D.
    • Proceedings of the National Academy of Sciences, Vol. 111, Issue 33
    • DOI: 10.1073/pnas.1405198111

    A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding
    journal, August 2003

    • Lin, P. -F.; Blair, W.; Wang, T.
    • Proceedings of the National Academy of Sciences, Vol. 100, Issue 19
    • DOI: 10.1073/pnas.1832214100

    Structural characterization of the human respiratory syncytial virus fusion protein core
    journal, December 2000

    • Zhao, X.; Singh, M.; Malashkevich, V. N.
    • Proceedings of the National Academy of Sciences, Vol. 97, Issue 26
    • DOI: 10.1073/pnas.260499197

    Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody
    journal, April 2013


    Phaedra, a Protocol-Driven System for Analysis and Validation of High-Content Imaging and Flow Cytometry
    journal, April 2012

    • Cornelissen, Frans; Cik, Miroslav; Gustin, Emmanuel
    • Journal of Biomolecular Screening, Vol. 17, Issue 4
    • DOI: 10.1177/1087057111432885

    The cost effectiveness of palivizumab: a systematic review of the evidence
    journal, July 2010


    Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity
    journal, March 2019


    Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state
    journal, February 2017

    • Rossey, Iebe; Gilman, Morgan S. A.; Kabeche, Stephanie C.
    • Nature Communications, Vol. 8, Issue 1
    • DOI: 10.1038/ncomms14158

    Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor
    journal, August 2017


    Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein
    journal, November 2017


    Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity
    journal, March 2019