TY  - JOUR
A1  - Maga, Giovanni
A1  - Garbelli, Anna
A1  - Radi, Marco
A1  - Falchi, Federico
A1  - Samuele, Alberta
A1  - Paolucci, Stefania
A1  - Baldanti, Fausto
A1  - Manetti, Fabrizio
A1  - Beermann, Sandra
A1  - Dietrich, Ursula
A1  - Botta, Maurizio
T1  - Next generation of antiretroviral agents targeting the RNA binding site of the HIV-1 cellular cofactor DDX3: an innovative therapeutic approach
T2  - Retrovirology
N2  - Introduction: 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.

Material and methods: Molecular modeling and in silico technologies were applied to rationally design small molecules specifically targeting the RNA binding site of human DDX3. Biochemical studies of mutated DDX3 enzymes were also used to identify additional potential drug binding sites.
Results

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.

Conclusions: We have identified the first inhibitors of HIV-1 replication targeting the RNA binding site of the cellular cofactor human DDX3. These compounds may offer superior selectivity over the ATP-competitive inhibitors previously developed. In addition, a novel RNA interacting motif specific to DDX3 has been identified, opening new venues for HIV-1 drug development.
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/24784
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-247849
UR  - http://www.retrovirology.com/content/9/S1/P5
SN  - 1742-4690
VL  - 9
IS  - (Suppl 1):P5
SP  - 1
EP  - 1
PB  - BioMed Central
CY  - London
ER  -