Novel Small Molecule Entry Inhibitors of Ebola Virus

Arnab Basu, Debra M. Mills, Daniel Mitchell, Esther Ndungo, John D. Williams, Andrew S. Herbert, John M. Dye, Donald T. Moir, Kartik Chandran, Jean L. Patterson, Lijun Rong, Terry L. Bowlin

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Background. The current Ebola virus (EBOV) outbreak has highlighted the troubling absence of available antivirals or vaccines to treat infected patients and stop the spread of EBOV. The EBOV glycoprotein (GP) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-EBOV drugs. We report the identification of 2 novel EBOV inhibitors targeting viral entry. Methods. To identify small molecule inhibitors of EBOV entry, we carried out a cell-based high-throughput screening using human immunodeficiency virus-based pseudotyped viruses expressing EBOV-GP. Two compounds were identified, and mechanism-of-action studies were performed using immunoflourescence, AlphaLISA, and enzymatic assays for cathepsin B inhibition. Results. We report the identification of 2 novel entry inhibitors. These inhibitors (1) inhibit EBOV infection (50% inhibitory concentration, approximately 0.28 and approximately 10 μmol/L) at a late stage of entry, (2) induce Niemann-Pick C phenotype, and (3) inhibit GP-Niemann-Pick C1 (NPC1) protein interaction. Conclusions. We have identified 2 novel EBOV inhibitors, MBX2254 and MBX2270, that can serve as starting points for the development of an anti-EBOV therapeutic agent. Our findings also highlight the importance of NPC1-GP interaction in EBOV entry and the attractiveness of NPC1 as an antifiloviral therapeutic target.

Original languageEnglish (US)
Pages (from-to)S425-S434
JournalJournal of Infectious Diseases
Volume212
DOIs
StatePublished - Oct 1 2015

Keywords

  • Ebola envelope glycoprotein
  • Ebola virus
  • Niemann-Pick C1
  • antiviral

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Basu, A., Mills, D. M., Mitchell, D., Ndungo, E., Williams, J. D., Herbert, A. S., Dye, J. M., Moir, D. T., Chandran, K., Patterson, J. L., Rong, L., & Bowlin, T. L. (2015). Novel Small Molecule Entry Inhibitors of Ebola Virus. Journal of Infectious Diseases, 212, S425-S434. https://doi.org/10.1093/infdis/jiv223