Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 01, 2016
- Source ID
- 10.1128/aac.00543-16
Entities
People
- Aaron R. Lindstrom
- Ajit Jadhav
- Andrey Kolokoltsov
- Anton Simeonov
- David J. Maloney
- Douglas J. Lacount
- Hang Wang
- Jennifer Kouznetsova
- Manu Anantpadma
- Olena Shtanko
- Rajarshi Guha
- Robert A Davey
- Ruili Huang
- Wendy Maury
Organizations
- Defense Threat Reduction Agency
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- Purdue University
- Texas Biomedical Research Institute
- University of Iowa
- University of Texas Medical Branch