A peptide nucleic acid-neamine conjugate that targets and cleaves HIV-1 TAR RNA inhibits viral replication

J Med Chem. 2004 Sep 23;47(20):4806-9. doi: 10.1021/jm049642d.

Abstract

The neamine part of the aminoglycoside antibiotic neomycin B was conjugated to a 16 mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. Attachment of the neamine core allows cellular uptake of the PNA and results in potent inhibition of HIV-1 replication. The polycationic neamine moiety imparts greater solubility to the PNA and also confers a unique RNA cleavage property to the conjugate which is specific to its target site and functional at physiological concentrations of Mg(2+). These properties suggest a potential therapeutic application for this class of compounds.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminoglycosides / chemistry
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • Binding Sites
  • Biochemistry / methods
  • Cells, Cultured
  • Drug Evaluation, Preclinical / methods
  • Framycetin
  • HIV Long Terminal Repeat / drug effects
  • HIV Long Terminal Repeat / genetics
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / virology
  • Peptide Nucleic Acids / chemistry*
  • Peptide Nucleic Acids / metabolism
  • Peptide Nucleic Acids / pharmacology*
  • RNA, Viral / drug effects
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • 12-(3,5-diamino-2-O-(2,6-diamino-2,6-dideoxyglucopyranosyl)-6-hydroxycyclohexyloxy)-1,6-diaza-2,5-dioxododecanyl-TCCCAGGCTCAGATCT-carboxamide
  • Aminoglycosides
  • Anti-HIV Agents
  • Peptide Nucleic Acids
  • RNA, Viral
  • Framycetin
  • neamine
  • HIV Reverse Transcriptase