The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses

IF 15.8 1区 医学 Q1 CELL BIOLOGY
David R. Martinez, Fernando R. Moreira, Nicholas J. Catanzaro, Meghan V. Diefenbacher, Mark R. Zweigart, Kendra L. Gully, Gabriela De la Cruz, Ariane J. Brown, Lily E. Adams, Boyd Yount, Thomas J. Baric, Michael L. Mallory, Helen Conrad, Samantha R. May, Stephanie Dong, D. Trevor Scobey, Cameron Nguyen, Stephanie A. Montgomery, Jason K. Perry, Darius Babusis, Kimberly T. Barrett, Anh-Hoa Nguyen, Anh-Quan Nguyen, Rao Kalla, Roy Bannister, Joy Y. Feng, Tomas Cihlar, Ralph S. Baric, Richard L. Mackman, John P. Bilello, Alexandra Schäfer, Timothy P. Sheahan
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引用次数: 0

Abstract

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 (Mpro) 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.
口服核苷原药 GS-5245 对 SARS-CoV-2 和其他地方性、流行性和流行性冠状病毒具有疗效。
尽管预防严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)的几种安全有效的疫苗已广泛使用,但能够逃避疫苗诱导免疫的严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)变异株(VOCs)的持续出现仍然是一个全球健康问题。此外,能够逃避治疗性单克隆抗体的 SARS-CoV-2 VOCs 的出现也凸显了对其他抗变异体治疗策略的需求。在这里,我们描述了 GS-5245 的抗病毒活性,即奥贝地西韦(ODV),它是母体核苷 GS-441524 的口服原药,靶向高度保守的病毒 RNA 依赖性 RNA 聚合酶(RdRp)。我们的研究表明,GS-5245 在体外对α-冠状病毒 HCoV-NL63、SARS-CoV、SARS-CoV 相关的蝙蝠-CoV RsSHC014、中东呼吸综合征冠状病毒 (MERS-CoV)、SARS-CoV-2 WA/1 和高传播性 SARS-CoV-2 BA.1 Omicron 变体具有广泛的效力。此外,在 SARS-CoV、SARS-CoV-2(WA/1 和 Omicron B1.1.529)、MERS-CoV 和蝙蝠-CoV RsSHC014 致病小鼠模型中,我们观察到 GS-5245 治疗可剂量依赖性地减少病毒复制、体重下降、急性肺损伤和肺功能。最后,我们证明了与单药相比,GS-5245 和主蛋白酶(Mpro)抑制剂 nirmatrelvir 的联合治疗可改善体内抗 SARS-CoV-2 的疗效。总之,我们的数据支持对 GS-5245 进行临床评估,以抗击引起或可能引起人类疾病的冠状病毒。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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