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

Marco Radi, Federico Falchi, Anna Garbelli, Alberta Samuele, Vincenzo Bernardo, Stefania Paolucci, Fausto Baldanti, Silvia Schenone, Fabrizio Manetti, Giovanni Maga, Maurizio Botta

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)2094-2098
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number5
Publication statusPublished - Mar 1 2012



  • Cofactor
  • DDX3
  • Helicase
  • HIV inhibitors
  • Homology modeling

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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