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

Gregory H. Bird, J. J. Patten, William Zavadoski, Nicole Barucci, Marina Godes, Benjamin M. Moyer, Callum D. Owen, Paul DaSilva-Jardine, Donna S. Neuberg, Richard A. Bowen, Robert A. Davey and Loren D. Walensky ()
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Gregory H. Bird: Dana-Farber Cancer Institute
J. J. Patten: Boston University
William Zavadoski: ATP R&D Labs
Nicole Barucci: ATP R&D Labs
Marina Godes: Dana-Farber Cancer Institute
Benjamin M. Moyer: Dana-Farber Cancer Institute
Callum D. Owen: Boston University
Paul DaSilva-Jardine: Red Queen Therapeutics, Inc.
Donna S. Neuberg: Dana-Farber Cancer Institute
Richard A. Bowen: Colorado State University
Robert A. Davey: Boston University
Loren D. Walensky: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44361-1

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