1. Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors.
- Author
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Capuzzi SJ, Sun W, Muratov EN, Martínez-Romero C, He S, Zhu W, Li H, Tawa G, Fisher EG, Xu M, Shinn P, Qiu X, García-Sastre A, Zheng W, and Tropsha A
- Subjects
- Animals, Antiviral Agents chemistry, Chlorocebus aethiops, Drug Discovery, Drug Evaluation, Preclinical, HeLa Cells, Humans, Molecular Structure, Quantitative Structure-Activity Relationship, Small Molecule Libraries chemistry, Vero Cells, Virus Internalization drug effects, Antiviral Agents pharmacology, Ebolavirus drug effects, Small Molecule Libraries pharmacology
- Abstract
The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC
50 values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.- Published
- 2018
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