title: A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading.
abstract: Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled-peptide scan across the HR2 domain of the respiratory syncytial virus (RSV) F protein with the aim to identify a minimal domain capable of disrupting the formation of the postfusion six-helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides that display nanomolar potency in HEp-2 cells and are exceptionally robust to proteolytic degradation. By replacing each amino acid of the peptides by an alanine, we found that the substitution of residues 506 to 509, located in a patch of polar contacts between HR2 and HR1, severely affected inhibition. Finally, we show that intranasal delivery of the most potent peptide to BALB/c mice significantly decreased RSV infection in upper and lower respiratory tracts. The discovery of this minimal HR2 sequence as a means for inhibition of RSV infection provides the basis for further medicinal chemistry efforts toward developing RSV fusion antivirals.
authors.affiliation: HES-SO Valais, Sion, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gaillard
authors.affiliation: VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Galloux
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva School of Medicine, CMU, Geneva, Switzerland.
authors.forename: Dominique
authors.identifier: 0000-0003-1556-897X
authors.initials: D
authors.lastname: Garcin
authors.affiliation: VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Eléouët
authors.affiliation: VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Ronan
authors.identifier: 0000-0002-2012-0064
authors.initials: R
authors.lastname: Le Goffic
authors.affiliation: INRA, UMR 703 APEX, Oniris, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Larcher
authors.affiliation: UMR INSERM U1173 I2, UFR des Sciences de la Santé Simone Veil-UVSQ, Montigny-Le-Bretonneux, France.|AP-HP, Laboratoire de Microbiologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Rameix-Welti
authors.affiliation: UMR INRA, Génétique Animale et Biologie Intégrative, Equipe plateforme @BRIDGE, plateau d'histologie, Jouy-en-Josas, France.
authors.forename: Abdelhak
authors.initials: A
authors.lastname: Boukadiri
authors.affiliation: HES-SO Valais, Sion, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Héritier
authors.affiliation: HES-SO Valais, Sion, Switzerland.
authors.forename: Jean-Manuel
authors.initials: JM
authors.lastname: Segura
authors.affiliation: HES-SO Valais, Sion, Switzerland.
authors.forename: Elodie
authors.initials: E
authors.lastname: Baechler
authors.affiliation: HES-SO Valais, Sion, Switzerland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Arrell
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva School of Medicine, CMU, Geneva, Switzerland.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Mottet-Osman
authors.affiliation: HES-SO Valais, Sion, Switzerland origene.nyanguile@hevs.ch.
authors.forename: Origène
authors.identifier: 0000-0003-1516-1109
authors.initials: O
authors.lastname: Nyanguile
mesh_terms: D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D059748:Proteolysis; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014760:Viral Fusion Proteins / Q000737:chemistry*; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C526850:F protein, human respiratory syncytial virus; D010455:Peptides; D014760:Viral Fusion Proteins
keywords: respiratory syncytial virus; stapled peptides