2 research outputs found
Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors
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<sub>50</sub> 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
Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors
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<sub>50</sub> 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