SARS-CoV-2 is causing a pandemic of COVID-19, with high infectivity and significant mortality¹. Currently, therapeutic options for COVID-19 are limited. Historically, metal compounds have found use as antimicrobial agents, but their antiviral activities have rarely been explored. Here, we test a set of metallodrugs and related compounds, and identify ranitidine bismuth citrate, a commonly used drug for the treatment of Helicobacter pylori infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo. Ranitidine bismuth citrate exhibited low cytotoxicity and protected SARS-CoV-2-infected cells with a high selectivity index of 975. Importantly, ranitidine bismuth citrate suppressed SARS-CoV-2 replication, leading to decreased viral loads in both upper and lower respiratory tracts, and relieved virus-associated pneumonia in a golden Syrian hamster model. In vitro studies showed that ranitidine bismuth citrate and its related compounds exhibited inhibition towards both the ATPase (IC₅₀ = 0.69 µM) and DNA-unwinding (IC₅₀ = 0.70 µM) activities of the SARS-CoV-2 helicase via an irreversible displacement of zinc(ii) ions from the enzyme by bismuth(iii) ions. Our findings highlight viral helicase as a druggable target and the clinical potential of bismuth(iii) drugs or other metallodrugs for the treatment of SARS-CoV-2 infection.

SARS-CoV-2导致COVID-19大流行，传染性高，死亡率高¹。目前，COVID-19的治疗选择有限。从历史上看，金属化合物已被用作抗菌剂，但很少研究其抗病毒活性。在这里，我们测试了一组金属药物和相关化合物，并确定了雷尼替丁柠檬酸铋（一种用于治疗幽门螺杆菌的常用药物）作为一种有效的抗SARS-CoV-2药物，可在体内和体外感染。柠檬酸雷尼替丁铋表现出低细胞毒性，受SARS-CoV-2感染的细胞受到保护，选择性指数高达975。重要的是，柠檬酸雷尼替丁铋抑制了SARS-CoV-2的复制，从而导致上下呼吸道的病毒载量降低，在金色的叙利亚仓鼠模型中缓解了与病毒有关的肺炎。体外研究表明，雷尼替丁柠檬酸铋铋及其相关化合物 对SARS-CoV-2解旋酶的ATP酶（IC ₅₀  = 0.69 µM）和DNA解绕（IC ₅₀ = 0.70 µM）活性具有不可逆的置换作用，具有抑制作用。锌（II）从通过铋酶离子（三）离子。我们的发现强调了病毒解旋酶是可治疗的靶标，以及铋（iii）药物或其他金属药物在治疗SARS-CoV-2感染中的临床潜力。