Identification of HIV-1 Inhibitors Targeting the Nucleocapsid Protein

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• 作者：Sebastian Breuer ; Max W. Chang ; Jinyun Yuan ; Bruce E. Torbett
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：4968-4977
• 全文大小：456K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

The HIV-1 nucleocapsid (NC) is a RNA/DNA binding protein encoded within the Gag polyprotein, which is critical for the selection and chaperoning of viral genomic RNA during virion assembly. RNA/DNA binding occurs through a highly conserved zinc-knuckle motif present in NC. Given the necessity of NC鈥搗iral RNA/DNA interaction for viral replication, identification of compounds that disrupt the NC鈥揜NA/DNA interaction may have value as an antiviral strategy. To identify small molecules that disrupt NC鈥搗iral RNA/DNA binding, a high-throughput fluorescence polarization assay was developed and a library of 14鈥?00 diverse, druglike compounds was screened. Compounds that disrupted NC binding to a fluorescence-labeled DNA tracer were next evaluated by differential scanning fluorimetry to identify compounds that must bind to NC or Gag to impart their effects. Two compounds were identified that inhibited NC鈥揇NA interaction, specifically bound NC with nanomolar affinity, and showed modest anti-HIV-1 activity in ex vivo cell assays.