Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection Article Swipe
Jared Pitts
,
Darius Babusis
,
Meghan S. Vermillion
,
Raju Subramanian
,
Kim Barrett
,
Diane S. Lye
,
Bin Ma
,
Xiaofeng Zhao
,
Nicholas C. Riola
,
Xuping Xie
,
Adriana E. Kajon
,
Xianghan Lu
,
Roy Bannister
,
Pei‐Yong Shi
,
Maria M. Toteva
,
Danielle Porter
,
Bill J. Smith
,
Tomáš Cihlář
,
Richard L. Mackman
,
John P. Bilello
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1016/j.antiviral.2022.105329
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1016/j.antiviral.2022.105329
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of <10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1016/j.antiviral.2022.105329
- OA Status
- hybrid
- Cited By
- 11
- References
- 30
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4229025386
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4229025386Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1016/j.antiviral.2022.105329Digital Object Identifier
- Title
-
Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infectionWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2022Year of publication
- Publication date
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2022-05-04Full publication date if available
- Authors
-
Jared Pitts, Darius Babusis, Meghan S. Vermillion, Raju Subramanian, Kim Barrett, Diane S. Lye, Bin Ma, Xiaofeng Zhao, Nicholas C. Riola, Xuping Xie, Adriana E. Kajon, Xianghan Lu, Roy Bannister, Pei‐Yong Shi, Maria M. Toteva, Danielle Porter, Bill J. Smith, Tomáš Cihlář, Richard L. Mackman, John P. BilelloList of authors in order
- Landing page
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https://doi.org/10.1016/j.antiviral.2022.105329Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
-
hybridOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.1016/j.antiviral.2022.105329Direct OA link when available
- Concepts
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In vivo, Potency, African Green Monkey, Pharmacology, Dosing, Bioavailability, Medicine, Respiratory system, Pharmacokinetics, Virology, In vitro, Virus, Immunology, Biology, Internal medicine, Biochemistry, BiotechnologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
11Total citation count in OpenAlex
- Citations by year (recent)
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2025: 6, 2024: 3, 2023: 2Per-year citation counts (last 5 years)
- References (count)
-
30Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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