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

Bioorg Med Chem Lett. 2012 Mar 1;22(5):2094-8. doi: 10.1016/j.bmcl.2011.12.135. Epub 2012 Jan 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Binding Sites / drug effects
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / metabolism*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • HIV Infections / drug therapy
  • HIV Infections / enzymology
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • RNA, Viral / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Viral Load / drug effects
  • Virus Replication / drug effects


  • Anti-HIV Agents
  • Enzyme Inhibitors
  • RNA, Viral
  • Small Molecule Libraries
  • Adenosine Triphosphatases
  • DEAD-box RNA Helicases