A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential.

Autor: Bird GH; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Patten JJ; Department of Microbiology, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA., Zavadoski W; ATP R&D Labs, Branford, CT, 06405, USA., Barucci N; ATP R&D Labs, Branford, CT, 06405, USA., Godes M; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Moyer BM; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Owen CD; Department of Microbiology, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA., DaSilva-Jardine P; Red Queen Therapeutics, Inc., Cambridge, MA, 02142, USA., Neuberg DS; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Bowen RA; Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523, USA., Davey RA; Department of Microbiology, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA., Walensky LD; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. Loren_Walensky@dfci.harvard.edu.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. Loren_Walensky@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jan 04; Vol. 15 (1), pp. 274. Date of Electronic Publication: 2024 Jan 04.
DOI: 10.1038/s41467-023-44361-1
Abstrakt: The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the biophysical and pharmacologic liabilities of peptides have hindered their clinical development. Here, we develop a chemically stapled lipopeptide inhibitor of SARS-CoV-2 as proof-of-concept for the platform. We show that our lead compound blocks infection by a spectrum of SARS-CoV-2 variants, exhibits mucosal persistence upon nasal administration, demonstrates enhanced stability compared to prior analogs, and mitigates infection in hamsters. We further demonstrate that our stapled lipopeptide platform yields nanomolar inhibitors of respiratory syncytial, Ebola, and Nipah viruses by targeting heptad-repeat-1 domains, which exhibit strikingly low mutation rates, enabling on-demand therapeutic intervention to combat viral outbreaks.
(© 2024. The Author(s).)
Databáze: MEDLINE
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