Details

Autor(en) / Beteiligte

• Capuzzi, Stephen J
• Sun, Wei
• Muratov, Eugene N
• Martínez-Romero, Carles
• He, Shihua
• Zhu, Wenjun
• Li, Hao
• Tawa, Gregory
• Fisher, Ethan G
• Xu, Miao
• Shinn, Paul
• Qiu, Xiangguo
• García-Sastre, Adolfo
• Zheng, Wei
• Tropsha, Alexander

Titel

Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2018-04, Vol.61 (8), p.3582-3594

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.