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; Robert A Davey

doi:10.1016/j.isci.2022.104925

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

iScience. 2022 Sep 16;25(9):104925. doi: 10.1016/j.isci.2022.104925. Epub 2022 Aug 13.

Authors

J J Patten¹, Patrick T Keiser¹, Deisy Morselli-Gysi^{2

3}, Giulia Menichetti^{2

3}, Hiroyuki Mori¹, Callie J Donahue¹, Xiao Gan^{2

3}, Italo do Valle², Kathleen Geoghegan-Barek¹, Manu Anantpadma¹, RuthMabel Boytz¹, Jacob L Berrigan¹, Sarah H Stubbs¹, Tess Ayazika¹, Colin O'Leary⁴, Sallieu Jalloh¹, Florence Wagner⁵, Seyoum Ayehunie⁶, Stephen J Elledge⁴, Deborah Anderson¹, Joseph Loscalzo³, Marinka Zitnik⁷, Suryaram Gummuluru¹, Mark N Namchuk⁸, Albert-László Barabási^{2

3

9}, Robert A Davey¹

Affiliations

¹ Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA.
² Network Science Institute, Northeastern University, Boston, MA 02115, USA.
³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Genetics, Program in Virology, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA, USA.
⁵ Center for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ MatTek Corporation, A BICO Company, Ashland, MA 01721, USA.
⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Network and Data Science, Central European University, Budapest 1051, Hungary.

Abstract

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.

Keywords: Bioinformatics; Pharmacoinformatics; Pharmacology; Virology.

Abstract

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