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.
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|Titolo:||Discovery of the first small molecule inhibitor of human DDX3 specifically designed to target the RNA binding site: towards the next generation HIV-1 inhibitors|
|Rivista:||BIOORGANIC & MEDICINAL CHEMISTRY LETTERS|
|Citazione:||Botta, M., Falchi, F., Garbelli, A., Samuele, A., Bernardo, V., Paolucci, S., et al. (2012). Discovery of the first small molecule inhibitor of human DDX3 specifically designed to target the RNA binding site: towards the next generation HIV-1 inhibitors. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 22(5), 2094-2098.|
|Appare nelle tipologie:||1.1 Articolo in rivista|