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Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products in vitro (preprint)
biorxiv; 2020.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2020.12.13.420406
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 M. 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 and S-G614]) 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.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Main subject:
Coronavirus Infections
/
Severe Acute Respiratory Syndrome
/
COVID-19
Language:
English
Year:
2020
Document Type:
Preprint
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