Abstract
AbstractRemdesivir 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.
Funder
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference46 articles.
1. U.S. Food & Drug Administration. FDA Approves First Treatment for COVID-19. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19 (last accessed 06/06/2021), 2020).
2. Mackman, R. L. et al. Prodrugs of a 1′-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV. J. Med. Chem. 64, 5001–5017 (2021).
3. Siegel, D. Discovery and Synthesis of a Phosphoramidate Prodrugof a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for theTreatment of Ebola and Emerging Viruses. J. Med. Chem 60, 1648–1661 (2017).
4. Meganck, R. M. & Baric, R. S. Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases. Nat. Med. 27, 401–410 (2021).
5. Toots, M. et al. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci. Transl. Med. 11, eaax5866 (2019).
Cited by
84 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献