Identification Of Potent Inhibitors Of Sars-Cov-2 Infection By Combined Pharmacological Evaluation And Cellular Network Prioritization

J.J. Patten, Patrick T. Keiser, Deisy Morselli-Gysi, Giulia Menichetti, Hiroyuki Mori, Callie J. Donahue, Xiao Gan, Italo Do Valle, Kathleen Geoghegan-Barek, Manu Anantpadma, Ruthmabel Boytz, Jacob L. Berrigan, Sarah H. Stubbs, Tess Ayazika, Colin O’leary, Sallieu Jalloh, Florence Wagner, Seyoum Ayehunie, Stephen J. Elledge, Deborah Anderson, Joseph Loscalzo, Marinka Zitnik, Suryaram Gummuluru, Mark N. Namchuk, Albert-László Barabási And Robert A. Davey


Pharmacologically active compounds with known biological targets were evaluated for inhibition of SARS-CoV-2 infection in cell and tissue models to help identify 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 between 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 activities, 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 establishes a rigorous approach for future pharmacological and computational identification of host factor dependencies and treatments for viral diseases.

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