Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products in vitro

Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. To screen for antiviral drugs for COVID-19 treatment, we constructed a SARS-CoV-2 spike (S) pseudovirus system using an HIV-1-based lentiviral vector wi...

Full description

Saved in:
Bibliographic Details
Published in:bioRxiv 2021-02
Main Authors: Chang-Long, He, Lu-Yi, Huang, Wang, Kai, Chen-Jian, Gu, Hu, Jie, Gui-Ji, Zhang, Xu, Wei, You-Hua, Xie, Tang, Ni, Ai-Long, Huang
Format: Article
Language:English
Subjects:
Alkaloids
Antiviral agents
Calcium
Cell lines
Coronaviridae
Coronaviruses
COVID-19
Drug development
HIV
Human immunodeficiency virus
Membrane fusion
Natural products
Public health
Reporter gene
Severe acute respiratory syndrome coronavirus 2
Online Access:Request full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. To screen for antiviral drugs for COVID-19 treatment, we constructed a SARS-CoV-2 spike (S) pseudovirus system using an HIV-1-based lentiviral vector with a luciferase reporter gene to screen 188 small potential antiviral compounds. Using this system, we identified nine compounds, specifically, bis-benzylisoquinoline alkaloids, that potently inhibited SARS-CoV-2 pseudovirus entry, with EC50 values of 0.1–10 μM. Mechanistic studies showed that these compounds, reported as calcium channel blockers (CCBs), inhibited Ca2+-mediated membrane fusion and consequently suppressed coronavirus entry. These candidate drugs showed broad-spectrum efficacy against the entry of several coronavirus pseudotypes (SARS-CoV, MERS-CoV, SARS-CoV-2 [S-D614, S-G614, N501Y.V1 and N501Y.V2]) in different cell lines (293T, Calu-3, and A549). Antiviral tests using native SARS-CoV-2 in Vero E6 cells confirmed that four of the drugs (SC9/cepharanthine, SC161/hernandezine, SC171, and SC185/neferine) reduced cytopathic effect and supernatant viral RNA load. Among them, cepharanthine showed the strongest anti-SARS-CoV-2 activity. Collectively, this study offers new lead compounds for coronavirus antiviral drug discovery. Competing Interest Statement The authors have declared no competing interest. Footnotes * S-pseudotyped coronaviruses including two emerging SARS-CoV-2 variants N501Y.V1 and N501Y.V2, reported in United Kingdom and South Africa, were tested. Figure 1 revised; Figures S1 to S4 revised;Table S1 to S2 updated.
DOI:10.1101/2020.12.13.420406