Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular (CV) side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor (GPCR) screening in combination with structural modeling and found that remdesivir is a selective agonist for urotensin-II receptor (UTS2R). Functionally, remdesivir treatment induced prolonged field potential in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and reduced contractility in neonatal rat cardiomyocytes, both of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants (SNVs) in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related CV events and that genetic variations of UTS2R gene can be a potential risk factor for CV events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.

中文翻译：

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抗 COVID-19 药物瑞德西韦激活 urotensin-II 受体诱导心肌细胞功能障碍

瑞德西韦是一种在全球范围内用于 COVID-19 治疗的抗病毒药物。心血管（CV）副作用与瑞德西韦有关；然而，潜在的分子机制仍然未知。在这里，我们结合结构建模进行了大规模的 G 蛋白偶联受体 (GPCR) 筛选，发现瑞德西韦是尿紧张素 II 受体 (UTS2R) 的选择性激动剂。在功能上，瑞德西韦治疗诱导人诱导多能干细胞 (iPS) 衍生心肌细胞的场电位延长，并降低新生大鼠心肌细胞的收缩性，这两者都反映了临床病理学。重要的是，瑞德西韦介导的心脏功能障碍通过拮抗 UTS2R 信号传导而得到有效减弱。最后，我们描述了 110 个单核苷酸变体 (SNV) 在UTS2R基因在基因组数据库中报告并发现了四种错义变体，这些变体在受体对瑞德西韦的敏感性中显示出功能获得效应。总的来说，我们的研究阐明了与瑞德西韦相关的心血管事件的一个以前未知的机制，并且UTS2R基因的遗传变异可能是瑞德西韦治疗期间心血管事件的潜在风险因素，这共同为预防此类事件的治疗机会铺平了道路。未来。