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. 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.
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Michael B
authors.identifier: http://orcid.org/0000-0002-5321-7460
authors.initials: MB
authors.lastname: Battles
authors.affiliation: Janssen Infectious Diseases and Vaccines, Leiden, the Netherlands.
authors.forename: Johannes P
authors.initials: JP
authors.lastname: Langedijk
authors.affiliation: Janssen Infectious Diseases and Vaccines, Leiden, the Netherlands.
authors.forename: Polina
authors.initials: P
authors.lastname: Furmanova-Hollenstein
authors.affiliation: Center for Vaccines &Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Supranee
authors.initials: S
authors.lastname: Chaiwatpongsakorn
authors.affiliation: Center for Vaccines &Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Costello
authors.affiliation: Respiratory Infections Research, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Kwanten
authors.affiliation: Respiratory Infections Research, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Vranckx
authors.affiliation: Discovery Sciences, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Vink
authors.affiliation: Discovery Sciences, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jaensch
authors.affiliation: Medicinal Chemistry Department, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Jonckers
authors.affiliation: Respiratory Infections Research, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.affiliation: Computational Chemistry, Janssen R&D LLC, Spring House, Pennsylvania, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Arnoult
authors.affiliation: Center for Vaccines &Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Peeples
authors.affiliation: Respiratory Infections Research, Janssen Infectious Diseases &Vaccines BVBA, Beerse, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Roymans
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay; D003124:Colorimetry; D006801:Humans; D008958:Models, Molecular; D060888:Real-Time Polymerase Chain Reaction; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D014760:Viral Fusion Proteins