Next generation of antiretroviral agents targeting the RNA binding site of the HIV-1 cellular cofactor DDX3: an innovative therapeutic approach

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. We have recently provided evidence for the possibility to block HIV-1 replication by targeting its cellular cofactor DDX3. Optimization of compounds identified by application of a high-throughput docking approach afforded a promising lead compound 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. A novel interaction site has been also identified in DDX3, which, when blocked, can reduce viral replication, representing an additional target for small molecules inhibitors.