Abstract
There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).
Highlights
Upon entry into the host cell cytoplasm, the viral genome is translated into roughly 30 proteins
We chose OC43 as it is a human pathogen that belongs to the same clade of beta-coronaviruses as SARS-CoV-2 and can be studied under “regular” biosafety conditions, as well as in an attempt to discover broad spectrum anti-coronavirus drugs that would be beneficial against SARS-CoV-2 and future emerging coronaviruses
Our results show that masitinib is a competitive inhibitor of 3CL, able to bind to the active site of the enzyme and inhibit its catalytic activity, both in vitro and in live cells
Summary
Upon entry into the host cell cytoplasm, the viral genome is translated into roughly 30 proteins. In a high biocontainment (BSL3) facility, A549 cells overexpressing the angiotensinconverting enzyme 2 (ACE2) receptor were treated with the drugs for 2 hours, infected with SARS-CoV-2 (nCoV/Washington/1/2020) at an MOI of 0.5, incubated for 2 days, fixed, and stained for the viral spike protein
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