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

Abstract

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.

Remdesivir-Related Cardiac Adverse Effects in COVID-19 Patients: A Case-Control Study

“…Despite the possibility of limitations due to the multifaceted nature of the occurrence of cardiac events, our results are consistent with prior reports of cardiac events in Remdesivir studies [26]. Ogawa et al discovered that Remdesivir activation of urotensin-II receptor causes electrophysiological abnormalities and strength of contraction deficits in cultured cardiomyocytes, resembling human cardiac side effects [27].…”

Severe Myocardium Suppression in Two Congenital Heart Disease Patients After Remdesivir Use

“…Remdesivir, instead, is reported to be a selective, partial agonist for urotensin-II receptor (UTS2R). The half-maximal effective concentration (pEC50) of remdesivir was estimated to be 4.89 ± 0.03 (EC50 = 13 ± 0.9 µM), with the working range of agonistic effects starting at 1 µM based on the response curve [12]. UTS2R, as a GPCR, in turn activates heterotrimeric G proteins, which leads to dissociation of Gα and Gβγ subunit complexes [13].…”

“…UTS2R, as a GPCR, in turn activates heterotrimeric G proteins, which leads to dissociation of Gα and Gβγ subunit complexes [13]. Possibly through impaired regulation of gene expression or tra cking of ERG potassium channels, eld potential, which correlates closely with the QT interval, is prolonged [12]. Remdesivir can also disturb the electrophysiological properties by reducing the spontaneous ring rate, which may lead to disruption in conduction system and development of ventricular premature complex, and the diastolic depolarization rate, which may lead to QRS widening [3].…”

“…Remdesivir can also disturb the electrophysiological properties by reducing the spontaneous ring rate, which may lead to disruption in conduction system and development of ventricular premature complex, and the diastolic depolarization rate, which may lead to QRS widening [3]. In addition, through binding to UTS2R, remdesivir can activate AKT/ERK axis [12]. Phosphorylation of ERK can in turn phosphorylate mitochondrial ssion dynamic-like protein 1 (Drp1) [14].…”