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

Author

Listed:
  • Gregory H. Bird

    (Dana-Farber Cancer Institute
    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
    Dana-Farber Cancer Institute)

  • Benjamin M. Moyer

    (Dana-Farber Cancer Institute
    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
    Dana-Farber Cancer Institute)

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.

Suggested Citation

  • 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 &, 2024. "A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44361-1
    DOI: 10.1038/s41467-023-44361-1
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    References listed on IDEAS

    as
    1. W. Weissenhorn & A. Dessen & S. C. Harrison & J. J. Skehel & D. C. Wiley, 1997. "Atomic structure of the ectodomain from HIV-1 gp41," Nature, Nature, vol. 387(6631), pages 426-430, May.
    2. Lu Lu & Qi Liu & Yun Zhu & Kwok-Hung Chan & Lili Qin & Yuan Li & Qian Wang & Jasper Fuk-Woo Chan & Lanying Du & Fei Yu & Cuiqing Ma & Sheng Ye & Kwok-Yung Yuen & Rongguang Zhang & Shibo Jiang, 2014. "Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
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