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Antimicrob Agents Chemother. 2016 Jul 22;60(8):4471-81. doi: 10.1128/AAC.00543-16. Print 2016 Aug.

Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors.

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Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, USA


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.

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