Activation of the urotensin-II receptor by anti-COVID-19 drug remdesivir induces cardiomyocyte dysfunction

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...

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Bibliographic Details
Published in:bioRxiv 2022-08
Main Authors: Fan-Yan, Wei, Inoue, Asuka, Ogawa, Akiko, Ohira, Seiya, Ikuta, Tatsuya, Kato, Yuri, Yanagida, Shota, Ishii, Yukina, Kanda, Yasunari, Nishida, Motohiro
Format: Article
Language:English
Subjects:
Cardiomyocytes
Coronaviruses
COVID-19
G protein-coupled receptors
Genetic diversity
Genomes
Muscle contraction
Neonates
Pluripotency
Receptor mechanisms
Risk factors
Stem cells
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Summary: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. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.08.08.503256