title: Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state.
abstract: Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV.
authors.affiliation: Medical Biotechnology Center, VIB, Technologiepark 927, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Iebe
authors.initials: I
authors.lastname: Rossey
authors.affiliation: Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755-3844, USA.
authors.forename: Morgan S A
authors.initials: MS
authors.lastname: Gilman
authors.affiliation: Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755-3844, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Kabeche
authors.affiliation: Medical Biotechnology Center, VIB, Technologiepark 927, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Sedeyn
authors.affiliation: Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755-3844, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wrapp
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Masaru
authors.identifier: 0000-0001-5767-1532
authors.initials: M
authors.lastname: Kanekiyo
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.affiliation: Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Mas
authors.affiliation: Medical Biotechnology Center, VIB, Technologiepark 927, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Spitaels
authors.affiliation: Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Melero
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.affiliation: Medical Biotechnology Center, VIB, Technologiepark 927, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Schepens
authors.affiliation: Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755-3844, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
authors.affiliation: Medical Biotechnology Center, VIB, Technologiepark 927, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D002161:Camelids, New World / Q000276:immunology; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000821:virology; D011485:Protein Binding; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology* / Q000502:physiology; D061905:Single-Domain Antibodies / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D061905:Single-Domain Antibodies; D014760:Viral Fusion Proteins