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.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
xuruolan发布了新的文献求助20
刚刚
刚刚
科研通AI2S应助LH采纳,获得10
1秒前
玩命的靖仇完成签到 ,获得积分10
1秒前
1秒前
1秒前
务实绿柏发布了新的文献求助10
1秒前
1秒前
2秒前
Echoes发布了新的文献求助10
2秒前
2秒前
沉静天思完成签到,获得积分10
4秒前
秋半梦发布了新的文献求助10
5秒前
5秒前
5秒前
liangmh发布了新的文献求助10
6秒前
宋德智发布了新的文献求助10
6秒前
澳大利亚马铃薯完成签到,获得积分10
7秒前
沉静天思发布了新的文献求助10
7秒前
谭显芝发布了新的文献求助10
7秒前
不爱干饭发布了新的文献求助10
7秒前
8秒前
杨气罐发布了新的文献求助10
8秒前
敏er好学完成签到,获得积分10
9秒前
开朗广山发布了新的文献求助10
10秒前
Jieao完成签到 ,获得积分10
11秒前
兰心哲发布了新的文献求助40
11秒前
12秒前
12秒前
小鱼发布了新的文献求助10
13秒前
liangmh完成签到,获得积分20
13秒前
Jasper应助祥梦伊飞采纳,获得10
14秒前
14秒前
14秒前
14秒前
16秒前
16秒前
Ava应助满眼星辰采纳,获得10
16秒前
娇羞的猛男完成签到,获得积分20
16秒前
高分求助中
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Chen Hansheng: China’s Last Romantic Revolutionary 500
宽禁带半导体紫外光电探测器 388
COSMETIC DERMATOLOGY & SKINCARE PRACTICE 388
Case Research: The Case Writing Process 300
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3142138
求助须知:如何正确求助?哪些是违规求助? 2793085
关于积分的说明 7805514
捐赠科研通 2449427
什么是DOI,文献DOI怎么找? 1303274
科研通“疑难数据库(出版商)”最低求助积分说明 626807
版权声明 601291