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Phosphorothioate oligonucleotides block the VDAC channel

Wenzhi Tan1, Yue-Hin Loke, C A Stein

  • 1Department of Biology, University of Maryland, College Park, Maryland 20742, USA.

Biophysical Journal
|May 8, 2007
PubMed

Insights

Phosphorothioate oligonucleotides like G3139 interact with voltage-dependent anion channels (VDAC), causing pore blockage. This interaction, dependent on sulfur atoms, influences metabolite flow and cell apoptosis.

Area of Science:

  • Mitochondrial biophysics
  • Molecular interactions
  • Drug discovery

Background:

  • Proapoptotic phosphorothioate oligonucleotides, such as G3139, induce apoptosis independently of Bcl-2.
  • These oligonucleotides may interact with the voltage-dependent anion channel (VDAC), reducing metabolite flow across the mitochondrial outer membrane.

Purpose of the Study:

  • To analyze the molecular-level interactions between phosphorothioate oligonucleotides and VDAC.
  • To elucidate the mechanism of VDAC pore blockage by G3139.

Main Methods:

  • Electrophysiological recordings of VDAC conductance in the presence of G3139.
  • Analysis of VDAC blockage kinetics, voltage-dependence, and concentration-dependence.
  • Comparison with a phosphodiester congener and a shorter oligonucleotide (polydeoxythymidine).

Main Results:

  • G3139 induces flickering and blockage of VDAC conductance, occurring in the open VDAC conformation.
  • Blockage is voltage-dependent (effective valence of -3) and concentration-dependent.
  • Kinetics suggest a two-state binding model: an unstable bound state causing flickering and a long-lived blocked state.
  • Polydeoxythymidine alters VDAC ion selectivity, indicating proximity to the ion stream.
  • The phosphodiester congener is ineffective, highlighting the role of sulfur atoms.

Conclusions:

  • Phosphorothioate oligonucleotides, particularly G3139, bind to VDAC, inducing a blockage.
  • The interaction involves sulfur atoms and is consistent with a binding-induced blockage mechanism.
  • These findings provide molecular insights into the interaction of oligonucleotides with VDAC and their proapoptotic effects.

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