Compound screen identifies the small molecule Q34 as an inhibitor of SARS-CoV-2 infection

Highlights

• A compound library was screened to identify inhibitors of SARS-CoV-2 cellular entry

• Small molecule Q34 is a potent inhibitor of cellular entry of pseudotyped SARS-CoV-2

• Compound Q34 inhibits authentic SARS-CoV-2 infection of human cells

• Compound Q34 is non-toxic to human cells without SARS-CoV-2 infection

Summary

The COVID-19 outbreak poses a serious threat to global public health. Effective countermeasures and approved therapeutics are desperately needed. In this study, we screened a small molecule library containing the NCI-DTP compounds to identify molecules that can prevent SARS-CoV-2 cellular entry. By applying a luciferase assay-based screening using a pseudotyped SARS-CoV-2-mediated cell entry assay, we identified a small molecule compound Q34 that can efficiently block cellular entry of the pseudotyped SARS-CoV-2 into human ACE2-expressing HEK293T cells, and inhibit the infection of the authentic SARS-CoV-2 in human ACE2-expressing HEK293T cells, human iPSC-derived neurons and astrocytes, and human lung Calu-3 cells. Importantly, the safety profile of the compound is favorable. There is no obvious toxicity observed in uninfected cells treated with the compound. Thus, this compound holds great potential as both prophylactics and therapeutics for COVID-19 and future pandemics by blocking the entry of SARS-CoV-2 and related viruses into human cells.