Abstract
A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / toxicity
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Cell Line, Tumor
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Computer Simulation
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DEAD-box RNA Helicases / antagonists & inhibitors*
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism
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Drug Design
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Drug Evaluation, Preclinical
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / toxicity
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Gene Knockdown Techniques
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HIV-1 / drug effects
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HIV-1 / enzymology
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Humans
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MicroRNAs / metabolism
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Rhodanine / chemical synthesis
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Rhodanine / chemistry
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Rhodanine / toxicity
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Structure-Activity Relationship
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Triazines / chemical synthesis
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Triazines / chemistry
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Triazines / toxicity
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Virus Replication / drug effects
Substances
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Anti-HIV Agents
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Enzyme Inhibitors
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MicroRNAs
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Triazines
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Rhodanine
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DEAD-box RNA Helicases