Double-Stapled Peptide Scan Yields Potent Fusion Inhibitors of Respiratory Syncytial Virus
Respiratory syncytial virus infection (RSV) is a major global health concern, particularly in infants and elderly populations. In this work, we have screened and identified 3 double-stapled peptides derived from a minimal domain of the RSV F heptad repeat, namely 3/4i, 3/4m, and 4/4g, which are potent inhibitors of RSV fusion and remain active against viral escape mutants resistant to small-molecule fusion inhibitors. Our structural activity relationship (SAR) analysis demonstrates that combining a limited set of staples is sufficient to achieve high antiviral potency. X-ray crystallography revealed that the enhanced potency of 3/4i and 3/4m primarily arises from strong hydrophobic interactions between the N-terminal staple and the trimeric HR1 coiled coil of RSV F. In vivo pharmacokinetic, imaging, and feasibility studies in RSV-infected Balb/c mice further support intranasal administration as a promising route for delivering these stapled peptides to the lung, highlighting their potential as therapeutics against RSV.
Authors
- Mathilde Keck (ORCID: https://orcid.org/0000-0003-4717-3446)
- Peggy Barbe
- Marie Galloux (ORCID: https://orcid.org/0000-0001-7477-8489)
- Dominique Garcin (ORCID: https://orcid.org/0000-0003-1556-897X)
- Geneviève Mottet-Osman
- S. Duquerroy (ORCID: https://orcid.org/0000-0003-4386-8013)
- Clémentine Prompt
- Nancy Nicolet
- Adrien Le Rouzic
- Roger Marti (ORCID: https://orcid.org/0000-0002-2135-7346)
- Felix Rey (ORCID: https://orcid.org/0000-0001-9082-780X)
- Logan Roh
- Marie-Anne Rameix-Welti
- Thibaut Larcher
- Jenna Fix
- Nadège Pidoux
- Origène Nyanguile (ORCID: https://orcid.org/0000-0003-1516-1109)
Institutions
- University of Geneva (CH)
- Institut National de la Recherche Agronomique (MA)
- Institut Pasteur (FR)
- HES-SO University of Applied Sciences and Arts Western Switzerland (CH)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Laboratoire de Mathématiques d'Orsay (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- School of Engineering and Architecture of Fribourg (CH)
- Technologies pour la Santé (FR)
- Laboratoire National de Référence (MA)
- HES-SO Valais-Wallis (CH)
- Apex School of Theology (US)
- Oniris (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02932
- Primary Topic
- Respiratory viral infections research
- Type
- article
- Field-Weighted Citation Impact
- 0.00