Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors

  • J Med Chem. 2018 Apr 26;61(8):3582-3594. doi: 10.1021/acs.jmedchem.8b00035.
Stephen J Capuzzi  1 ,  Wei Sun  2 ,  Eugene N Muratov  1  3 ,  Carles Martínez-Romero  4  5 ,  Shihua He  6 ,  Wenjun Zhu  6  7 ,  Hao Li  2 ,  Gregory Tawa  2 ,  Ethan G Fisher  2 ,  Miao Xu  2 ,  Paul Shinn  2 ,  Xiangguo Qiu  6  7 ,  Adolfo García-Sastre  4  5  8 ,  Wei Zheng  2 ,  Alexander Tropsha  1
Affiliations
  • 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.
PMID: 29624387 DOI: 10.1021/acs.jmedchem.8b00035
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.