Loading...
Identification of potent inhibitors of SARS-CoV-2 infection by combined pharmacological evaluation and cellular network prioritization
Title / Series / Name
Publication Volume
Publication Issue
Pages
Authors
Patten, J. J.
Keiser, Patrick T.
Morselli-Gysi, Deisy
Menichetti, Giulia
Mori, Hiroyuki
Donahue, Callie J.
Gan, Xiao
Valle, Italo do
Geoghegan-Barek, Kathleen
Anantpadma, Manu
Boytz, Ruth Mabel
Berrigan, Jacob L.
Stubbs, Sarah H.
Ayazika, Tess
O'Leary, Colin
Jalloh, Sallieu
Wagner, Florence
Ayehunie, Seyoum
Elledge, Stephen J.
Anderson, Deborah
Loscalzo, Joseph
Zitnik, Marinka
Gummuluru, Suryaram
Namchuk, Mark N.
Barabási, Albert László
Davey, Robert A.
Keiser, Patrick T.
Morselli-Gysi, Deisy
Menichetti, Giulia
Mori, Hiroyuki
Donahue, Callie J.
Gan, Xiao
Valle, Italo do
Geoghegan-Barek, Kathleen
Anantpadma, Manu
Boytz, Ruth Mabel
Berrigan, Jacob L.
Stubbs, Sarah H.
Ayazika, Tess
O'Leary, Colin
Jalloh, Sallieu
Wagner, Florence
Ayehunie, Seyoum
Elledge, Stephen J.
Anderson, Deborah
Loscalzo, Joseph
Zitnik, Marinka
Gummuluru, Suryaram
Namchuk, Mark N.
Barabási, Albert László
Davey, Robert A.
Editors
Keywords
Bioinformatics
Pharmacoinformatics
Pharmacology
Virology
Multidisciplinary
SDG 3 - Good Health and Well-being
Pharmacoinformatics
Pharmacology
Virology
Multidisciplinary
SDG 3 - Good Health and Well-being
URI
https://hdl.handle.net/20.500.14018/27135
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.
Topic
Publisher
Place of Publication
Type
Journal article
Date
2022-09-16
Language
ISBN
Identifiers
10.1016/j.isci.2022.104925