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J Med Chem. 2018 Apr 26;61(8):3582-3594. doi: 10.1021/acs.jmedchem.8b00035. Epub 2018 Apr 17.

Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors.

Author information

1
Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry , UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
2
National Center for Advancing Translational Sciences , National Institutes of Health , Bethesda , Maryland 20892 , United States.
3
Department of Chemical Technology , Odessa National Polytechnic University , Odessa 65000 , Ukraine.
4
Department of Microbiology , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
5
Global Health and Emerging Pathogens Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
6
Special Pathogens Program, National Microbiology Laboratory , Public Health Agency of Canada , 1015 Arlington Street , Winnipeg , Manitoba R3E 3R2 , Canada.
7
Department of Medical Microbiology , University of Manitoba , 745 Bannatyne Avenue , Winnipeg , Manitoba R3E 0J9 , Canada.
8
Department of Medicine, Division of Infectious Diseases , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.

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 IC50 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.

PMID:
29624387
PMCID:
PMC6548547
DOI:
10.1021/acs.jmedchem.8b00035
[Indexed for MEDLINE]
Free PMC Article

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