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

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 ?M, 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 ?M). 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.

SUBMITTER: Capuzzi SJ 

PROVIDER: S-EPMC6548547 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature