29qj | pdb_000029qj
Respiratory syncytial virus fusion protein N-terminal heptad repeat domain in complex with Double stapled peptide 4/4g
Structural highlights
FunctionFUS_HRSVA Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.[1] [2] Publication Abstract from PubMedRespiratory 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. Double-Stapled Peptide Scan Yields Potent Fusion Inhibitors of Respiratory Syncytial Virus.,Pidoux N, Roh L, Nicolet N, Marti R, Le Rouzic A, Prompt C, Fix J, Duquerroy S, Rey F, Rameix-Welti MA, Keck M, Barbe P, Garcin D, Mottet-Osman G, Larcher T, Galloux M, Nyanguile O J Med Chem. 2026 May 27. doi: 10.1021/acs.jmedchem.5c02932. PMID:42203199[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
