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

  • Giovanni Maga1Email author,
  • Anna Garbelli1,
  • Marco Radi2,
  • Federico Falchi2,
  • Alberta Samuele1,
  • Stefania Paolucci3,
  • Fausto Baldanti3,
  • Fabrizio Manetti2,
  • Sandra Beermann4,
  • Ursula Dietrich4 and
  • Maurizio Botta2
Retrovirology20129(Suppl 1):P5

Published: 25 May 2012


Interact MotifDrug Binding SitePromising LeadDocking ApproachViral Enzyme


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.


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.


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.

Authors’ Affiliations

Instituto di Genetica Molecolare, Pavia, Italy
Dipartimento Farmaco Chimico Tecnologico, University of Siena, Siena, Italy
Molecular Virology Unit, Foundation IRCCS Policlinico S. Matteo, piazzale Golgi, Pavia, Italy
Georg-Speyer-Haus Institute of Biomedical Research, Frankfurt, Germany


© Maga et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.