Remdesivir activates urotensin II receptor and induces cardiomyocyte dysfunction

In a recent study posted to the bioRxiv* preprint server, researchers assessed the cardiac effects of remdesivir.

Study: Activation of the urotensin-II receptor by anti-COVID-19 drug remdesivir induces cardiomyocyte dysfunction. Image Credit: felipe caparros/Shutterstock
Study: Activation of the urotensin-II receptor by anti-COVID-19 drug remdesivir induces cardiomyocyte dysfunction. Image Credit: felipe caparros/Shutterstock

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Background

Nucleoside analogs have been long used for designing antiviral drugs. Nucleoside analogs inhibit viral RNA-dependent RNA polymerase (RdRp). Several analogs, such as remdesivir, favipiravir, and molnupiravir, have been approved to treat coronavirus disease 2019 (COVID-19).

Remdesivir, a modified adenosine analog, is rapidly converted to a mono-nucleoside form upon intravenous administration. Subsequently, it is metabolized by host enzymes to the active triphosphate state. The active drug is a selective and potent inhibitor of RdRp of many viruses. Initially used for treating the Ebola virus, remdesivir was approved for COVID-19 amid the pandemic.

Although well tolerated by most patients, commonly reported adverse events include a rash, nausea, headache, and elevated transaminases. Moreover, cardiovascular events such as bradycardia, hypertension, T-wave abnormality, and QT prolongation have been reported.

Remdesivir distributes to multiple tissues, including the heart; however, the mechanisms underlying the cardiovascular complications remain unknown.

Molnupiravir and favipiravir have been used for COVID-19 treatment. Although different adverse events have been reported, no cardiovascular event has been reported with the use of favipiravir or molnupiravir. Nucleosides or nucleotides also act as ligands for G-protein-coupled receptors (GPCRs). As nucleoside analogs mimic structures, it is hypothesized that they could activate GPCRs and cause side effects.

The study and findings

In the present study, researchers carried out a large-scale GPCR screening using the three anti-COVID-19 drugs. The nucleoside analogs were screened against 348 GPCRs in a transforming growth factor (TGF)-α shedding assay. Initially, screening was performed using Gα subunits for efficient detection of receptor activation. The authors noted that remdesivir selectively activated the urotensin II receptor (UTS2R).

Concentration-response analysis showed a half-maximal effective concentration (pEC50) of 4.89 for remdesivir, albeit lower than that of urotensin II, the endogenous ligand of UTS2R. Intriguingly, remdesivir did not induce a β-arrestin recruitment response, unlike urotensin II, and thus was a G-protein-biased ligand. The major and minor metabolites of remdesivir, GS-441524, and GS-704277, did not affect the activation of UTS2R.

Further investigation revealed that receptor activation required both the nucleoside base and the McGuigan prodrug moiety of remdesivir. In silico structural docking of UTS2R and remdesivir identified multiple residues in the orthosteric pocket, potentially stabilizing binding to remdesivir. Three residues of UTS2R (T304, N297, and M134) were found to interact with remdesivir. Substituting these residues with others abolished the activation potency of remdesivir.

Next, HEK293 cells expressing UTS2R were stimulated with remdesivir, and the phosphorylation of extracellular signal regulation kinase (ERK) 1/2 was examined. Remdesivir treatment induced long-lasting phosphorylation of ERK1/2 in a dose-dependent manner. Remdesivir-mediated phosphorylation was abolished in the presence of a UTS2R antagonist.

The impact of remdesivir on cardiomyocytes was assessed given the high expression of UTS2R and urotensin II in cardiovascular systems. The drug’s effect was analyzed on the field potential (FP) using human-induced pluripotent stem (iPS) cell-derived cardiomyocytes, in which UTS2R levels are comparable to that of the heart.

A multielectrode assay showed that remdesivir-treated cells showed prolonged FP duration that was significantly suppressed in the presence of a UTS2R antagonist. The effects of the drug on cardiac contractility were assessed on neonatal rat cardiomyocytes (NRCMs). Chronic remdesivir application on NRCMs resulted in reduced contractility attenuated by UTS2R antagonist.

The team constructed 110 missense mutants corresponding to human single nucleotide variants (SNVs) in the UTS2R gene. Of these, 44 SNVs exhibited lower sensitivity to remdesivir relative to the wildtype receptor. In contrast, 47 SNVs had reduced sensitivity to urotensin II.

Notably, four missense SNVs increased sensitivity to remdesivir relative to wildtype. Of these, two SNVs had lower sensitivity to urotensin II, while the other two had a moderate/insignificant increase in sensitivity to urotensin II. Individuals with these mutations might be more susceptible to remdesivir/UTS2R-mediated cardiotoxicity.

Conclusions

The authors discovered that remdesivir selectively activated UTS2R. UTS2R activation by urotensin II has been implicated in cardiac dysfunction. As such, UTS2R activation by remdesivir in cultured cardiomyocytes induced electrical abnormalities and impaired contractility, resembling the reported cardiac events in humans. Notably, the adverse effects were negated by antagonizing UTS2R or blocking the downstream signaling.

The findings suggested that the clinical dose of remdesivir was adequate to trigger UTS2R activation. Notwithstanding the finding that UTS2R is activated by remdesivir leading to cardiotoxicity, a limitation of the study is the lack of clinical evidence.

In summary, the study provided mechanistic insights into remdesivir-mediated cardiac effects and discovered that it acts as a selective UTS2R agonist.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Journal references:

Article Revisions

  • May 15 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Sai Lomte, Tarun. (2023, May 15). Remdesivir activates urotensin II receptor and induces cardiomyocyte dysfunction. News-Medical. Retrieved on July 25, 2024 from https://www.news-medical.net/news/20220812/Remdesivir-activates-urotensin-II-receptor-and-induces-cardiomyocyte-dysfunction.aspx.

  • MLA

    Sai Lomte, Tarun. "Remdesivir activates urotensin II receptor and induces cardiomyocyte dysfunction". News-Medical. 25 July 2024. <https://www.news-medical.net/news/20220812/Remdesivir-activates-urotensin-II-receptor-and-induces-cardiomyocyte-dysfunction.aspx>.

  • Chicago

    Sai Lomte, Tarun. "Remdesivir activates urotensin II receptor and induces cardiomyocyte dysfunction". News-Medical. https://www.news-medical.net/news/20220812/Remdesivir-activates-urotensin-II-receptor-and-induces-cardiomyocyte-dysfunction.aspx. (accessed July 25, 2024).

  • Harvard

    Sai Lomte, Tarun. 2023. Remdesivir activates urotensin II receptor and induces cardiomyocyte dysfunction. News-Medical, viewed 25 July 2024, https://www.news-medical.net/news/20220812/Remdesivir-activates-urotensin-II-receptor-and-induces-cardiomyocyte-dysfunction.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
COVID-19 and metallic taste: Study connects immunoglobulin levels to sensory impairment