Journal article
Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors
Antimicrobial agents and chemotherapy, Vol.60(8), pp.4471-4481
08/2016
DOI: 10.1128/AAC.00543-16
PMCID: PMC4958205
PMID: 27161622
Abstract
Filoviruses are highly infectious, and no FDA-approved drug therapy for filovirus infection is available. Most work to find a treatment has involved only a few strains of Ebola virus and testing of relatively small drug libraries or compounds that have shown efficacy against other virus types. Here we report the findings of a high-throughput screening of 319,855 small molecules from the Molecular Libraries Small Molecule Repository library for their activities against Marburg virus and Ebola virus. Nine of the most potent, novel compounds that blocked infection by both viruses were analyzed in detail for their mechanisms of action. The compounds inhibited known key steps in the Ebola virus infection mechanism by blocking either cell surface attachment, macropinocytosis-mediated uptake, or endosomal trafficking. To date, very few specific inhibitors of macropinocytosis have been reported. The 2 novel macropinocytosis inhibitors are more potent inhibitors of Ebola virus infection and less toxic than ethylisopropylamiloride, one commonly accepted macropinocytosis inhibitor. Each compound blocked infection of primary human macrophages, indicating their potential to be developed as new antifiloviral therapies.
Details
- Title: Subtitle
- Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors
- Creators
- Manu Anantpadma - Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, USAJennifer Kouznetsova - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USAHang Wang - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USARuili Huang - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USAAndrey Kolokoltsov - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USARajarshi Guha - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USAAaron R Lindstrom - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USAOlena Shtanko - Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, USAAnton Simeonov - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USADavid J Maloney - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USAWendy Maury - Department of Microbiology, University of Iowa, Iowa City, Iowa, USADouglas J LaCount - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USAAjit Jadhav - National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USARobert A Davey - Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, USA rdavey@txbiomed.org
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.60(8), pp.4471-4481
- DOI
- 10.1128/AAC.00543-16
- PMID
- 27161622
- PMCID
- PMC4958205
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Grant note
- R03 MH086850 / NIMH NIH HHS R21 AI115082 / NIAID NIH HHS Z01 HG200319-05 / Intramural NIH HHS R01 AI114814 / NIAID NIH HHS R01 AI077519 / NIAID NIH HHS
- Language
- English
- Date published
- 08/2016
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083878402771
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