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

doi:10.1016/j.bmcl.2011.12.135

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.

Authors

Marco Radi¹, Federico Falchi, Anna Garbelli, Alberta Samuele, Vincenzo Bernardo, Stefania Paolucci, Fausto Baldanti, Silvia Schenone, Fabrizio Manetti, Giovanni Maga, Maurizio Botta

Affiliation

¹ Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.

PMID: 22300661
DOI: 10.1016/j.bmcl.2011.12.135

Abstract

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

Substances

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