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[Preprint]. 2020 Jul 27:2020.05.23.112235.
doi: 10.1101/2020.05.23.112235.

Bepridil is potent against SARS-CoV-2 In Vitro

Erol C Vatansever  1 , Kai Yang  1 , Kaci C Kratch  1 , Aleksandra Drelich  2 , Chia-Chuan Cho  1 , Drake M Mellott  3 , Shiqing Xu  1 , Chien-Te K Tseng  2 , Wenshe Ray Liu  1   3   4
Affiliations

Bepridil is potent against SARS-CoV-2 In Vitro

Erol C Vatansever et al. bioRxiv. .

Update in

  • Bepridil is potent against SARS-CoV-2 in vitro.
    Vatansever EC, Yang KS, Drelich AK, Kratch KC, Cho CC, Kempaiah KR, Hsu JC, Mellott DM, Xu S, Tseng CK, Liu WR. Vatansever EC, et al. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2012201118. doi: 10.1073/pnas.2012201118. Proc Natl Acad Sci U S A. 2021. PMID: 33597253 Free PMC article.

Abstract

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 μM. 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 μM and in A549 cells completely at and dose-dependently below 6.25 μM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

Keywords: COVID-19; SARS-CoV-2; bepridil; drug repurposing; main protease.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.

Figures

Figure 1:
Figure 1:
Structures of 29 FDA/EMA-approved medicines and rupintrivir whose IC50 values in inhibiting MPro were determined in the study.
Figure 2:
Figure 2:
Activity of MPro. (A) The structures of three substrates. (B) Activity of 50 nM MPro on 10 μM Sub1. (C) Activity of 50 nM MPro on 10 μM Sub2 and Sub3. The florescence signals are normalized for easy comparison. (D) Activity of different concentrations of MPro on 10 μM Sub3.
Figure 3:
Figure 3:
Initial screening of Mpro inhibition by 29 FDA/EMA-approved medicines and rupintrivir. 1 mM (0.14 mM for Itraconazole due to its low solubility in DMSO) was used for each inhibitor to perform the inhibition assay. Fluorescence intensity was normalized with respect to the control that had no small molecule provided. Triplicate experiments were performed for each compound, and the value was presented as mean ± standard error (SE).
Figure 4:
Figure 4:
IC50 assays for 18 small molecule medicines on their inhibition of Mpro. Triplicate experiments were performed for each compound, and the IC50 value was presented as mean ± standard error (SE). GraphPad Prism 8.0 was used to perform data analysis.
Figure 5:
Figure 5:
Pimozide (A), ebastine (B), bepridil (C), and their overlay (D) in the active site of MPro. The protein surface topography in A, B, and C is presented to show the concaved active site.
See this image and copyright information in PMC

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