IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26760-4.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26760-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26760-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. 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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    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. Bruno A. Rodriguez-Rodriguez & Grace O. Ciabattoni & Ralf Duerr & Ana M. Valero-Jimenez & Stephen T. Yeung & Keaton M. Crosse & Austin R. Schinlever & Lucie Bernard-Raichon & Joaquin Rodriguez Galvan , 2023. "A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. S. Jaumdally & M. Tomasicchio & A. Pooran & A. Esmail & A. Kotze & S. Meier & L. Wilson & S. Oelofse & C. Merwe & A. Roomaney & M. Davids & T. Suliman & R. Joseph & T. Perumal & A. Scott & M. Shaw & W, 2024. "Frequency, kinetics and determinants of viable SARS-CoV-2 in bioaerosols from ambulatory COVID-19 patients infected with the Beta, Delta or Omicron variants," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26760-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.