title: Novel Small Molecule Entry Inhibitors of Ebola Virus.
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.
authors.affiliation: Microbiotix, Inc, Worcester, Massachusetts.
authors.forename: Arnab
authors.initials: A
authors.lastname: Basu
authors.affiliation: Microbiotix, Inc, Worcester, Massachusetts.
authors.forename: Debra M
authors.initials: DM
authors.lastname: Mills
authors.affiliation: Texas Biomedical Research Institute, San Antonio.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mitchell
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Esther
authors.initials: E
authors.lastname: Ndungo
authors.affiliation: Microbiotix, Inc, Worcester, Massachusetts.
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.affiliation: Army Medical Research Institute of Infectious Diseases, Frederick, Maryland.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Herbert
authors.affiliation: Army Medical Research Institute of Infectious Diseases, Frederick, Maryland.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: Microbiotix, Inc, Worcester, Massachusetts.
authors.forename: Donald T
authors.initials: DT
authors.lastname: Moir
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Kartik
authors.initials: K
authors.lastname: Chandran
authors.affiliation: Texas Biomedical Research Institute, San Antonio.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Patterson
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago.
authors.forename: Lijun
authors.initials: L
authors.lastname: Rong
authors.affiliation: Microbiotix, Inc, Worcester, Massachusetts.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000187:drug effects*; D006023:Glycoproteins / Q000378:metabolism; D057809:HEK293 Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014709:Vero Cells; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D054852:Small Molecule Libraries
keywords: Ebola envelope glycoprotein; Ebola virus; Niemann-Pick C1; antiviral