RT Journal Article
SR Electronic
T1 Activation of the urotensin-II receptor by anti-COVID-19 drug remdesivir induces cardiomyocyte dysfunction
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.08.503256
DO 10.1101/2022.08.08.503256
A1 Ogawa, Akiko
A1 Ohira, Seiya
A1 Ikuta, Tatsuya
A1 Kato, Yuri
A1 Yanagida, Shota
A1 Ishii, Yukina
A1 Kanda, Yasunari
A1 Nishida, Motohiro
A1 Inoue, Asuka
A1 Wei, Fan-Yan
YR 2022
UL http://biorxiv.org/content/early/2022/08/09/2022.08.08.503256.abstract
AB 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.One Sentence Summary Remdesivir‘s activity as a selective agonist of urotensin-II receptor underlies its known cardiotoxicity in anti-viral therapy.Competing Interest StatementThe authors have declared no competing interest.