Identification of potent inhibitors of SARS-CoV-2 infection by combined pharmacological evaluation and cellular network prioritization

Pharmacologically active compounds with known biological targets were evalu-ated for inhibition of SARS-CoV-2 infection in cell and tissue models to help iden-tify potent classes of active small molecules and to better understand host-virus interactions. We evaluated 6,710 clinical and preclinical compounds targeting 2,183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships be-tween small molecule structure, dose-response antiviral activity, host target, and cell interactome produced cellular networks important for infection. This analysis revealed 389 small molecules with micromolar to low nanomolar activ-ities, representing >12 scaffold classes and 813 host targets. Representatives were evaluated for mechanism of action in stable and primary human cell models with SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work es-tablishes a rigorous approach for future pharmacological and computational iden-tification of host factor dependencies and treatments for viral diseases.

Automated summary

The study evaluated pharmacologically active compounds with known biological targets for inhibiting SARS-CoV-2 infection. Through cell and tissue models, they identified several active small molecules and gained insights into host-virus interactions. The findings provide a rigorous approach for identifying potential treatments for viral diseases through the evaluation of host factor dependencies.