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Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

Author

Listed:
  • Robert M. Cox

    (Georgia State University)

  • Josef D. Wolf

    (Georgia State University)

  • Carolin M. Lieber

    (Georgia State University)

  • Julien Sourimant

    (Georgia State University)

  • Michelle J. Lin

    (University of Washington)

  • Darius Babusis

    (Gilead Sciences Inc)

  • Venice DuPont

    (Gilead Sciences Inc)

  • Julie Chan

    (Gilead Sciences Inc)

  • Kim T. Barrett

    (Gilead Sciences Inc)

  • Diane Lye

    (Gilead Sciences Inc)

  • Rao Kalla

    (Gilead Sciences Inc)

  • Kwon Chun

    (Gilead Sciences Inc)

  • Richard L. Mackman

    (Gilead Sciences Inc)

  • Chengjin Ye

    (Texas Biomedical Research Institute)

  • Tomas Cihlar

    (Gilead Sciences Inc)

  • Luis Martinez-Sobrido

    (Texas Biomedical Research Institute)

  • Alexander L. Greninger

    (University of Washington)

  • John P. Bilello

    (Gilead Sciences Inc)

  • Richard K. Plemper

    (Georgia State University)

Abstract

Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.

Suggested Citation

  • Robert M. Cox & Josef D. Wolf & Carolin M. Lieber & Julien Sourimant & Michelle J. Lin & Darius Babusis & Venice DuPont & Julie Chan & Kim T. Barrett & Diane Lye & Rao Kalla & Kwon Chun & Richard L. M, 2021. "Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26760-4
    DOI: 10.1038/s41467-021-26760-4
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    References listed on IDEAS

    as
    1. Mathilde Richard & Adinda Kok & Dennis Meulder & Theo M. Bestebroer & Mart M. Lamers & Nisreen M. A. Okba & Martje Fentener van Vlissingen & Barry Rockx & Bart L. Haagmans & Marion P. G. Koopmans & Ro, 2020. "SARS-CoV-2 is transmitted via contact and via the air between ferrets," Nature Communications, Nature, vol. 11(1), pages 1-6, December.
    2. Jasmin S. Kutter & Dennis Meulder & Theo M. Bestebroer & Pascal Lexmond & Ard Mulders & Mathilde Richard & Ron A. M. Fouchier & Sander Herfst, 2021. "SARS-CoV and SARS-CoV-2 are transmitted through the air between ferrets over more than one meter distance," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
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    Cited by:

    1. Carolin M. Lieber & Robert M. Cox & Julien Sourimant & Josef D. Wolf & Kate Juergens & Quynh Phung & Manohar T. Saindane & Meghan K. Smith & Zachary M. Sticher & Alexander A. Kalykhalov & Michael G. N, 2022. "SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Michael H. J. Rhodin & Archie C. Reyes & Anand Balakrishnan & Nalini Bisht & Nicole M. Kelly & Joyce Sweeney Gibbons & Jonathan Lloyd & Michael Vaine & Tessa Cressey & Miranda Crepeau & Ruichao Shen &, 2024. "The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Robert M. Cox & Carolin M. Lieber & Josef D. Wolf & Amirhossein Karimi & Nicole A. P. Lieberman & Zachary M. Sticher & Pavitra Roychoudhury & Meghan K. Andrews & Rebecca E. Krueger & Michael G. Natchu, 2023. "Comparing molnupiravir and nirmatrelvir/ritonavir efficacy and the effects on SARS-CoV-2 transmission in animal models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Yuxia Lin & Mona Khan & Birgit Weynand & Manon Laporte & Frank Coenjaerts & Darius Babusis & John P. Bilello & Peter Mombaerts & Dirk Jochmans & Johan Neyts, 2024. "A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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