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Nat Chem Biol. 2016 Feb;12(2):87-93. doi: 10.1038/nchembio.1982. Epub 2015 Dec 7.

Molecular mechanism of respiratory syncytial virus fusion inhibitors.

Author information

1
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
2
Janssen Infectious Diseases and Vaccines, Leiden, the Netherlands.
3
Center for Vaccines &Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
4
Respiratory Infections Research, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
5
Discovery Sciences, Janssen Pharmaceutica NV, Beerse, Belgium.
6
Medicinal Chemistry Department, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
7
Computational Chemistry, Janssen R&D LLC, Spring House, Pennsylvania, USA.
8
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.

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. Here 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. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

PMID:
26641933
PMCID:
PMC4731865
DOI:
10.1038/nchembio.1982
[Indexed for MEDLINE]
Free PMC Article

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