Heart drug Vascor shows significant efficacy in interfering with SARS-CoV-2 entry into human cell host

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A federally approved heart medication shows significant effectiveness in interfering with SARS-CoV-2 entry into the human cell host, according to a new study by a research team from Texas A&M University and The University of Texas Medical Branch (UTMB).

The medication bepridil, which goes by the trade name Vascor, is currently approved by the U.S. Food and Drug Administration (FDA) to treat angina, a heart condition.

The team’s leaders are College of Science professor Wenshe Ray Liu, professor and holder of the Gradipore Chair in the Department of Chemistry at Texas A&M, and Chien-Te Kent Tseng, professor and director of the SARS/MERS/COVID-19 Laboratory at UTMB. Liu also holds joint faculty positions in Texas A&M’s colleges of medicine and agriculture and life sciences.

“Only one medication is currently available, Remdesivir, to provide limited benefits to COVID-19 patients, and the virus may easily evade it,” Liu said.

“Finding alternative medicines is imperative. Our team screened more than 30 FDA/European Medicines Agency approved drugs for their ability to inhibit SARS-COV-2’s entry into human cells. The study found bepridil to offer the most potential for treatment of COVID-19. As a result, we are advocating for the serious consideration of using bepridil in clinical tests related to SARS-CoV-2.”

The Texas A&M-UTMB study is now available at the website of the peer-reviewed Proceedings of the National Academy of Sciences (PNAS) and is scheduled for print publication on March 9.

The team, which includes six other researchers from Texas A&M and four from UTMB, now plans to advance their work to animal models with a potential for clinical trials.


Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100

mM. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in

COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-

2 entry into the human cell host and inhibiting MPro in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS- CoV-2 in Vero E6 cells completely at and dose-dependently below 5 mM and in A549 cells completely at and dose-dependently below 6.25 mM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

. . . . . From cell biology point of view, our three lead compounds share similarities with some proposed COVID-19 treatment options. There are reports on the investigation of using hydroxychloroquine to treat COVID-19 patients.(31, 32) A likely mechanism of action for hydroxychloroquine is its ability to raise endosomal pH that impacts significantly activities of endosomal proteases that may be required to process the virus membrane proteins.(33, 34)

Our top three hits pimozide, ebastine, and bepridil are all basic small molecules that can potentiate a similar effect.(35) Among the three drugs, bepridil can be very interesting because it previously provided 100% protection from Ebola virus infections in mice at a dose of 12 mg/kg.(36) Bepridil is a calcium channel blocker with a significant anti-anginal activity. For patients with chronic stable angina, recommended daily dose of bepridil is 200-400 mg.(29)

Mice administered with a bepridil dose as high as 300 mg/kg/day did not show alteration in mating behavior and reproductive performance, indicating that bepridil has very low toxicity.(37) Moreover, a previous study showed that bepridil can increase the pH of acidic endosomes.(38)

Administration of a high dose of bepridil may have dual functions to slow down the virus replication in host cells by both inhibiting MPro and raising the pH of endosomes. To demonstrate this prospect, we conducted a live virus-based microneutralization assay to evaluate efficacy of pimozide, ebastine and bepridil in their inhibition of SARS-CoV-2 infection in Vero E6 cells. Vero E6 is a cell line isolated kidney epithelial cells from African Green Monkey.

We tested three medicines in a concentration range from 0.16 to 200 mM. Cytopathogenic effect (CPE) was clearly observable for pimozide and ebastine at all tested concentrations. However, bepridil prevented completely the SARS-CoV-2- induced CPE in Vero E6 cells when the concentration reached 5 mM and inhibited CPE in a dose dependent manner below 5 mM (Table 3A). It did not display cellular toxicity until the concentration reached 50 mM.

A parallel test in A549 cells that were derived from human alveolar epithelial cells showed that bepridil prevented SARS-CoV-2-induced CPE completely at 6.25 mM and inhibited CPE in a dose dependent manner below 6.25 mM but did not display a cytotoxic effect when the concentration reached 200 mM (Table 3B). The complete prevention of SARS- CoV-2-induced CPE in Vero E6 and A549 cells by bepridil at a concentration much lower than its IC50 value for inhibiting MPro is likely due to the aforementioned dual functions or other cellular

effects of bepridil. In patients, bepridil can reach a state Cmax as 3.72 mM.(39) This concentration is effective in inhibiting SARS-CoV-2 based on our virus microneutralization analysis. Collectively, our results indicate that bepridil is effective in preventing SARS-CoV-2 from entry and replication in mammalian cell hosts. Therefore, we urge clinical tests of bepridil in the treatment of COVID-19.

CONCLUSION

Guided by a computational docking analysis, we experimentally characterized about 30 FDA/EMA-approved drugs on their inhibition of the essential MPro enzyme of the COVID-19 pathogen SARS-CoV-2. From the study, we identified six FDA/EMA-approved drugs that can potently inhibit MPro with an IC50 value lower than 100 µM.

One medicine bepridil exhibited strong inhibition of SARS-CoV-2 from entry and replication inside Vero E6 cells at a low micromolar concentration. Given that bepridil has been previously explored to treat Ebola infected patients, we urge a serious consideration of its clinical tests in treating COVID-19.

Our current study indicates that there is a large amount of FDA/EMA-approved drug space open for exploration that could hold promise for repurposing existing drugs to target COVID-19. Performing screening studies on different SARS-CoV-2 protein targets are necessary to uncover existing medicines that may be combined for cocktail treatments of COVID-19. More explorations in this direction are imperative.

reference link: https://doi.org/10.1101/2020.05.23.112235


More information: Erol C. Vatansever et al, Bepridil is potent against SARS-CoV-2 in vitro, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2012201118

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