Potassium-dependent folding: a key to intracellular delivery of G-quartet oligonucleotides as HIV inhibitors

Biochemistry. 2002 Apr 30;41(17):5397-403. doi: 10.1021/bi0120401.


Several groups have demonstrated that G-rich oligonucleotides forming G-quartet structures display activity as potential drugs, such as potent HIV inhibitors. The delivery of G-quartet oligonucleotides to their intracellular targets is a key obstacle to overcome for their clinical success. Here we have developed a novel system to deliver G-rich oligonucleotides into the cell nucleus, e.g., the site of HIV integration. On the basis of the property of potassium-induced formation of G-quartet structure, we explored the difference of K(+) concentrations inside (140 mM) and outside (4 mM) cells to induce the G-rich oligonucleotides to form different structures inside and outside cells. The key steps of this delivery system include the following: (i) First, the G-quartet structure is denatured to form a lipid-DNA complex, so that the molecules can be well delivered into cells. (ii) Then the delivered molecules are induced to form G-quartet structures by potassium inside cells since the G-quartet structure is the primary requirement for inhibition of HIV-1 HIV integrase (IN) activity. The molecules of a novel G-quartet HIV inhibitor, T40214, with the sequence of (GGGC)(4) were successfully delivered into the nuclei of target cells, which significantly decreased HIV-1 replication and increased the probability to target HIV-1 IN in infected cells.

Publication types

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

MeSH terms

  • Cell Line
  • DNA / chemistry
  • DNA / metabolism
  • Drug Carriers / chemistry
  • Drug Carriers / metabolism
  • Drug Delivery Systems / methods*
  • Guanine / chemistry
  • Guanine / metabolism*
  • Guanine / pharmacology
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / metabolism*
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / physiology
  • Humans
  • Intracellular Fluid / metabolism*
  • Kinetics
  • Liposomes
  • Macromolecular Substances
  • Nucleic Acid Conformation*
  • Nucleic Acid Denaturation
  • Oligodeoxyribonucleotides / chemistry
  • Oligodeoxyribonucleotides / metabolism*
  • Oligodeoxyribonucleotides / pharmacology
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / metabolism
  • Potassium / chemistry*
  • Virus Integration / drug effects
  • Virus Replication / drug effects


  • Drug Carriers
  • HIV Integrase Inhibitors
  • Liposomes
  • Macromolecular Substances
  • Oligodeoxyribonucleotides
  • Phosphatidylethanolamines
  • Guanine
  • 1,2-dielaidoylphosphatidylethanolamine
  • DNA
  • Potassium