iScience (Sep 2022)
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
Affiliations
- J.J. Patten
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Patrick T. Keiser
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Deisy Morselli-Gysi
- Network Science Institute, Northeastern University, Boston, MA 02115, USA; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Giulia Menichetti
- Network Science Institute, Northeastern University, Boston, MA 02115, USA; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Hiroyuki Mori
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Callie J. Donahue
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Xiao Gan
- Network Science Institute, Northeastern University, Boston, MA 02115, USA; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Italo do Valle
- Network Science Institute, Northeastern University, Boston, MA 02115, USA
- Kathleen Geoghegan-Barek
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Manu Anantpadma
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- RuthMabel Boytz
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Jacob L. Berrigan
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Sarah H. Stubbs
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Tess Ayazika
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Colin O’Leary
- Department of Genetics, Program in Virology, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA, USA
- Sallieu Jalloh
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Florence Wagner
- Center for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
- Seyoum Ayehunie
- MatTek Corporation, A BICO Company, Ashland, MA 01721, USA
- Stephen J. Elledge
- Department of Genetics, Program in Virology, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA, USA
- Deborah Anderson
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Joseph Loscalzo
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Marinka Zitnik
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
- Suryaram Gummuluru
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA
- Mark N. Namchuk
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
- Albert-László Barabási
- Network Science Institute, Northeastern University, Boston, MA 02115, USA; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Network and Data Science, Central European University, Budapest 1051, Hungary
- Robert A. Davey
- Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA 02118, USA; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 9
p. 104925
Abstract
Summary: 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.
