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

  • 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.

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Author:Giovanni Maga, Anna Garbelli, Marco Radi, Federico Falchi, Alberta Samuele, Stefania Paolucci, Fausto Baldanti, Fabrizio Manetti, Sandra BeermannGND, Ursula Dietrich, Maurizio Botta
URN:urn:nbn:de:hebis:30:3-247849
URL:http://www.retrovirology.com/content/9/S1/P5
DOI:https://doi.org/doi:10.1186/1742-4690-9-S1-P5
ISSN:1742-4690
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/22453133
Parent Title (English):Retrovirology
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2012/05/25
Date of first Publication:2012/05/25
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2012/05/29
Volume:9
Issue:(Suppl 1):P5
Page Number:1
First Page:1
Last Page:1
HeBIS-PPN:432173722
Institutes:Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0