Abstract
RNA-protein interactions are vital throughout the HIV-1 life cycle for the successful production of infectious virus particles. One such essential RNA-protein interaction occurs between the full-length genomic viral RNA and the major structural protein of the virus. The initial interaction is between the Gag polyprotein and the viral RNA packaging signal (psi or Ψ), a highly conserved RNA structural element within the 5'-UTR of the HIV-1 genome, which has gained attention as a potential therapeutic target. Here, we report the application of a target-based assay to identify small molecules, which modulate the interaction between Gag and Ψ. We then demonstrate that one such molecule exhibits potent inhibitory activity in a viral replication assay. The mode of binding of the lead molecules to the RNA target was characterized by ¹H NMR spectroscopy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / adverse effects
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology*
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Binding Sites
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Cell Survival / drug effects
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Drug Evaluation, Preclinical
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HEK293 Cells
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HIV Infections / drug therapy
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HIV-1 / drug effects*
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HIV-1 / physiology
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HeLa Cells
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Humans
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Models, Molecular
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Molecular Targeted Therapy
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Nucleic Acid Conformation / drug effects
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Nucleic Acid Denaturation / drug effects
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Osmolar Concentration
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Quinolinium Compounds / adverse effects
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Quinolinium Compounds / chemistry
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Quinolinium Compounds / pharmacology
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RNA, Spliced Leader / drug effects*
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RNA, Viral / antagonists & inhibitors*
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RNA, Viral / chemistry
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RNA, Viral / metabolism
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Ribonucleoproteins / antagonists & inhibitors*
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Ribonucleoproteins / chemistry
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Ribonucleoproteins / metabolism
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Schiff Bases / adverse effects
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Schiff Bases / chemistry
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Schiff Bases / pharmacology
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Small Molecule Libraries
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Virus Replication / drug effects*
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gag Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
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gag Gene Products, Human Immunodeficiency Virus / metabolism
Substances
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Anti-HIV Agents
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NSC-260594
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Quinolinium Compounds
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RNA, Spliced Leader
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RNA, Viral
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Ribonucleoproteins
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Schiff Bases
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Small Molecule Libraries
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gag Gene Products, Human Immunodeficiency Virus