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Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential

病毒学 冠状病毒 冠状病毒科 生物 体内 核苷 病毒 前药 中东呼吸综合征 抗病毒药物 大流行 免疫学 医学 疾病 2019年冠状病毒病(COVID-19) 药理学 传染病(医学专业) 生物技术 病理 生物化学
作者
David R. Martinez,Fernando R. Moreira,Mark R. Zweigart,Kendra Gully,Gabriela De la Cruz,Ariane J. Brown,Lily E. Adams,Nicholas Catanzaro,Boyd Yount,Thomas J. Baric,Michael L. Mallory,Helen Conrad,Samantha R. May,Stephanie Dong,D. Trevor Scobey,Stephanie A. Montgomery,Jason K. Perry,Darius Babusis,Kimberly T. Barrett,An Nguyẽ̂n,Anh-Quan Nguyen,Rao Kalla,Roy Bannister,John P. Bilello,Joy Y. Feng,Tomáš Cihlář,Ralph S. Baric,Richard L. Mackman,Alexandra Schäfer,Timothy P. Sheahan
标识
DOI:10.1101/2023.06.27.546784
摘要

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective 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 RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (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 in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

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