Molecular mechanism of respiratory syncytial virus fusion inhibitors

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.

doi:10.1038/nchembio.1982

Title: Molecular mechanism of respiratory syncytial virus fusion inhibitors

Journal Article · Mon Dec 07 00:00:00 EST 2015 · Nature Chemical Biology

DOI:https://doi.org/10.1038/nchembio.1982· OSTI ID:1239404

^[1]; Langedijk, Johannes P. ^[2]; Furmanova-Hollenstein, Polina ^[2]; Chaiwatpongsakorn, Supranee ^[3]; Costello, Heather M. ^[3]; Kwanten, Leen ^[4]; Vranckx, Luc ^[4]; Vink, Paul ^[5]; Jaensch, Steffen ^[5]; Jonckers, Tim H. M. ^[6]; Koul, Anil ^[4]; Arnoult, Eric ^[7]; Peeples, Mark E. ^[8]; Roymans, Dirk ^[4]; McLellan, Jason S. ^[1]

Geisel School of Medicine at Dartmouth, Hanover, NH (United States). Dept. of Biochemistry
Janssen Infectious Diseases and Vaccines, Leiden (Netherlands)
The Research Inst. at Nationwide Children's Hospital, Columbus, OH (United States). Center for Vaccines & Immunity
Janssen Infectious Diseases & Vaccines BVBA, Beerse (Belgium). Respiratory Infections Research
Janssen Pharmaceutica NV, Beerse (Belgium). Discovery Sciences
Janssen Infectious Diseases & Vaccines BVBA, Beerse (Belgium). Medicinal Chemistry Dept.
Janssen R&D LLC, Spring House, PA (United States). Computational Chemistry
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

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.

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Research Organization:: Geisel School of Medicine at Dartmouth, Hanover, NH (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health (NIH) (United States); Charles H. Hood Foundation (United States)

Contributing Organization:: 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)

Grant/Contract Number:: AC02-06CH11357; AI 095684

OSTI ID:: 1239404

Journal Information:: Nature Chemical Biology, Vol. 12, Issue 2; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 87 works

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