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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:
Journal Article: 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 = {Mon Dec 07 00:00:00 EST 2015},
month = {Mon Dec 07 00:00:00 EST 2015}
}

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