A short double-stapled peptide inhibits respiratory syncytial virus entry and spreading
| Autor: | Geneviève Mottet-Osman, Origène Nyanguile, Elodie Baechler, Miriam Arrell, Abdelhak Boukadiri, Ronan Le Goffic, Marie Galloux, Julien Héritier, Thibaut Larcher, Marie-Anne Rameix-Welti, Jean-Manuel Segura, Vanessa Gaillard, Dominique Garcin, Jean-François Eléouët |
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| Přispěvatelé: | Haute École Spécialisée de Suisse occidentale Valais (HES-SO Valais-Wallis), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Department of Microbiology and Molecular Medicine, University of Geneva [Switzerland], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Laboratoire de Microbiologie, Hôpital Raymond Poincareé, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Commission for Technology and Innovation CTI [12.868.1], Swiss Confederation, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, UFR des Sciences de la Santé Simone Veil |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Protein Conformation alpha-Helical viruses respiratory syncytial virus [SDV]Life Sciences [q-bio] Peptide Plasma protein binding Respiratory syncytial virus stapled peptides Virus Replication respiratory syncytial viruses Mice Pharmacology (medical) Peptide sequence chemistry.chemical_classification ddc:616 Mice Inbred BALB C Protein Stability virus respiratoire syncytial 3. Good health Amino acid Stapled peptides Infectious Diseases Female Protein Binding Respiratory Syncytial Virus Infections Biology Antiviral Agents Virus 03 medical and health sciences Viral entry Animals Humans Protein Interaction Domains and Motifs Amino Acid Sequence Administration Intranasal Pharmacology Binding Sites Sequence Homology Amino Acid Virus Internalization Virology Heptad repeat 030104 developmental biology chemistry Viral replication Amino Acid Substitution Respiratory Syncytial Virus Human Proteolysis Peptides Sequence Alignment Viral Fusion Proteins HeLa Cells |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2017, 61 (4), ⟨10.1128/AAC.02241-16⟩ Antimicrobial Agents and Chemotherapy, Vol. 61, No 4 (2017) Antimicrobial Agents and Chemotherapy 4 (61), . (2017) |
| ISSN: | 0066-4804 1098-6596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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