دورية أكاديمية
The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.
| العنوان: | The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses. |
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| المؤلفون: | Martinez DR; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.; Yale Center for Infection and Immunity, Yale School of Medicine, New Haven, CT 06510, USA., Moreira FR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Catanzaro NJ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Diefenbacher MV; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Zweigart MR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Gully KL; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., De la Cruz G; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA., Brown AJ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Adams LE; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Yount B; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Baric TJ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Mallory ML; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Conrad H; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., May SR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Dong S; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Scobey DT; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Nguyen C; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Montgomery SA; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA., Perry JK; Gilead Sciences, Inc., Foster City, CA 94404, USA., Babusis D; Gilead Sciences, Inc., Foster City, CA 94404, USA., Barrett KT; Gilead Sciences, Inc., Foster City, CA 94404, USA., Nguyen AH; Gilead Sciences, Inc., Foster City, CA 94404, USA., Nguyen AQ; Gilead Sciences, Inc., Foster City, CA 94404, USA., Kalla R; Gilead Sciences, Inc., Foster City, CA 94404, USA., Bannister R; Gilead Sciences, Inc., Foster City, CA 94404, USA., Feng JY; Gilead Sciences, Inc., Foster City, CA 94404, USA., Cihlar T; Gilead Sciences, Inc., Foster City, CA 94404, USA., Baric RS; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Mackman RL; Gilead Sciences, Inc., Foster City, CA 94404, USA., Bilello JP; Gilead Sciences, Inc., Foster City, CA 94404, USA., Schäfer A; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Sheahan TP; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. |
| المصدر: | Science translational medicine [Sci Transl Med] 2024 May 22; Vol. 16 (748), pp. eadj4504. Date of Electronic Publication: 2024 May 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | SARS-CoV-2*/drug effects , Prodrugs*/pharmacology , Prodrugs*/therapeutic use , Antiviral Agents*/pharmacology , Antiviral Agents*/therapeutic use, Animals ; Humans ; Mice ; Administration, Oral ; Chlorocebus aethiops ; Vero Cells ; COVID-19 Drug Treatment ; COVID-19/virology ; Virus Replication/drug effects ; Nucleosides/pharmacology ; Nucleosides/therapeutic use ; Nucleosides/chemistry ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Female ; Disease Models, Animal |
| مستخلص: | Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (M pro ) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease. |
| التعليقات: | Update of: bioRxiv. 2023 Jun 28:2023.06.27.546784. doi: 10.1101/2023.06.27.546784. (PMID: 37425890) |
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| معلومات مُعتمدة: | R01 AI132178 United States AI NIAID NIH HHS; U19 AI171292 United States AI NIAID NIH HHS |
| المشرفين على المادة: | 0 (Prodrugs) 0 (Antiviral Agents) 0 (Nucleosides) |
| SCR Organism: | SARS-CoV-2 variants |
| تواريخ الأحداث: | Date Created: 20240522 Date Completed: 20240522 Latest Revision: 20240821 |
| رمز التحديث: | 20240821 |
| مُعرف محوري في PubMed: | PMC11333937 |
| DOI: | 10.1126/scitranslmed.adj4504 |
| PMID: | 38776389 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.adj4504 |