Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys Article Swipe
Richard L. Mackman
,
Rao Kalla
,
Darius Babusis
,
Jared Pitts
,
Kimberly T. Barrett
,
Kwon Soo Chun
,
Venice Du Pont
,
Lauren Rodriguez
,
Jasmine Moshiri
,
Yili Xu
,
Michael Lee
,
Gary Lee
,
Blake J. Bleier
,
Anh-Quan Nguyen
,
B. Michael O’Keefe
,
Andrea Ambrosi
,
Meredith Cook
,
Joy Yu
,
Elodie Dempah
,
Elaine Bunyan
,
Nicholas C. Riola
,
Xianghan Lu
,
Renmeng Liu
,
Ashley Davie
,
Tien-Ying Hsiang
,
Michael Gale
,
Anita Niedziela‐Majka
,
Joy Y. Feng
,
Charlotte Hedskog
,
John P. Bilello
,
Raju Subramanian
,
Tomáš Cihlář
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.04.28.538473
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.04.28.538473
Remdesivir 1 is an amidate prodrug that releases the monophosphate of nucleoside GS-441524 ( 2 ) into lung cells thereby forming the bioactive triphosphate 2-NTP . 2-NTP , an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP . Here we describe the discovery of a 5’-isobutyryl ester prodrug of 2 ( GS-5245, Obeldesivir, 3 ) that has low cellular cytotoxicity and three to seven-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved pre-systemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice-daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2 which supports development of 3 as a promising COVID-19 treatment.
Related Topics
Concepts
Prodrug
Nucleoside
Pharmacology
Virology
RNA
Nucleoside triphosphate
Virus
RNA polymerase
Nucleoside analogue
Chemistry
Biology
Medicine
Nucleotide
Biochemistry
Gene
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2023.04.28.538473
- https://www.biorxiv.org/content/biorxiv/early/2023/04/28/2023.04.28.538473.full.pdf
- OA Status
- green
- Cited By
- 11
- References
- 39
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4367296223
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4367296223Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2023.04.28.538473Digital Object Identifier
- Title
-
Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green MonkeysWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-04-28Full publication date if available
- Authors
-
Richard L. Mackman, Rao Kalla, Darius Babusis, Jared Pitts, Kimberly T. Barrett, Kwon Soo Chun, Venice Du Pont, Lauren Rodriguez, Jasmine Moshiri, Yili Xu, Michael Lee, Gary Lee, Blake J. Bleier, Anh-Quan Nguyen, B. Michael O’Keefe, Andrea Ambrosi, Meredith Cook, Joy Yu, Elodie Dempah, Elaine Bunyan, Nicholas C. Riola, Xianghan Lu, Renmeng Liu, Ashley Davie, Tien-Ying Hsiang, Michael Gale, Anita Niedziela‐Majka, Joy Y. Feng, Charlotte Hedskog, John P. Bilello, Raju Subramanian, Tomáš CihlářList of authors in order
- Landing page
-
https://doi.org/10.1101/2023.04.28.538473Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2023/04/28/2023.04.28.538473.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.biorxiv.org/content/biorxiv/early/2023/04/28/2023.04.28.538473.full.pdfDirect OA link when available
- Concepts
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Prodrug, Nucleoside, Pharmacology, Virology, RNA, Nucleoside triphosphate, Virus, RNA polymerase, Nucleoside analogue, Chemistry, Biology, Medicine, Nucleotide, Biochemistry, GeneTop concepts (fields/topics) attached by OpenAlex
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11Total citation count in OpenAlex
- Citations by year (recent)
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2025: 6, 2024: 4, 2023: 1Per-year citation counts (last 5 years)
- References (count)
-
39Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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