Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (5), p.2094-2098
2012
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Details
- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (5), p.2094-2098
- Ort / Verlag
- Amsterdam: Elsevier Ltd
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-894XeISSN: 1464-3405DOI: 10.1016/j.bmcl.2011.12.135Titel-ID: cdi_proquest_miscellaneous_926901175
- Format
- –
- Schlagworte
- Adenosine Triphosphatases - metabolism, adenosinetriphosphatase, Anti-HIV Agents - chemistry, Anti-HIV Agents - pharmacology, Antibiotics. Antiinfectious agents. Antiparasitic agents, antiretroviral agents, Antiviral agents, binding sites, Binding Sites - drug effects, Biological and medical sciences, chemotherapy, Cofactor, DDX3, DEAD-box RNA helicases, DEAD-box RNA Helicases - antagonists & inhibitors, DEAD-box RNA Helicases - chemistry, DEAD-box RNA Helicases - metabolism, drug resistance, drugs, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Helicase, HIV infections, HIV Infections - drug therapy, HIV Infections - enzymology, HIV inhibitors, HIV-1 - drug effects, HIV-1 - physiology, Homology modeling, Human immunodeficiency virus, Human immunodeficiency virus 1, Humans, Leukocytes, Mononuclear - drug effects, Leukocytes, Mononuclear - virology, Medical sciences, mononuclear leukocytes, mutation, Pharmacology. Drug treatments, RNA, RNA, Viral - metabolism, Small Molecule Libraries - chemistry, Small Molecule Libraries - pharmacology, viral load, Viral Load - drug effects, Virus Replication - drug effects