Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 5, Pages 2094-2098Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.12.135
Keywords
HIV inhibitors; Homology modeling; Helicase; DDX3; Cofactor
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Funding
- 6th FP Excellent-Hit Consortium [LSHP-CT-2006-037257]
- Italian National Research Programme on AIDS [40H26]
- Ministero della Sanita, Fondazione IRCCS Policlinico San Matteo, Ricerca [80622]
- Tuscany Region
- Franca Rame and Dario Fo'' Nobel Foundation
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Efficacy of currently approved anti-HIV drugs is hampered by mutations of the viral enzymes, leading invariably to drug resistance and chemotherapy failure. Recent data suggest that cellular co-factors also represent useful targets for anti-HIV therapy. Here we describe the identification of the first small molecules specifically designed to inhibit the HIV-1 replication by targeting the RNA binding site of the human DEAD-Box RNA helicase DDX3. Optimization of a easily synthetically accessible hit (1) identified by application of a high-throughput docking approach afforded the promising compounds 6 and 8 which proved to inhibit both the helicase and ATPase activity of DDX3 and to reduce the viral load of peripheral blood mononuclear cells (PBMC) infected with HIV-1. (C) 2012 Elsevier Ltd. All rights reserved.
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