Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides

Antimicrob Agents Chemother. 2006 Mar;50(3):1034-44. doi: 10.1128/AAC.50.3.1034-1044.2006.

Abstract

Although transmissible spongiform encephalopathies (TSEs) are incurable, a key therapeutic approach is prevention of conversion of the normal, protease-sensitive form of prion protein (PrP-sen) to the disease-specific protease-resistant form of prion protein (PrP-res). Here degenerate phosphorothioate oligonucleotides (PS-ONs) are introduced as low-nM PrP-res conversion inhibitors with strong antiscrapie activities in vivo. Comparisons of various PS-ON analogs indicated that hydrophobicity and size were important, while base composition was only minimally influential. PS-ONs bound avidly to PrP-sen but could be displaced by sulfated glycan PrP-res inhibitors, indicating the presence of overlapping binding sites. Labeled PS-ONs also bound to PrP-sen on live cells and were internalized. This binding likely accounts for the antiscrapie activity. Prophylactic PS-ON treatments more than tripled scrapie survival periods in mice. Survival times also increased when PS-ONs were mixed with scrapie brain inoculum. With these antiscrapie activities and their much lower anticoagulant activities than that of pentosan polysulfate, degenerate PS-ONs are attractive new compounds for the treatment of TSEs.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Base Composition
  • Cell Line
  • Cricetinae
  • Hydrophobic and Hydrophilic Interactions
  • Inhibitory Concentration 50
  • Injections, Intraperitoneal
  • Injections, Subcutaneous
  • Mice
  • Mice, Transgenic
  • Molecular Weight
  • Nucleic Acid Conformation
  • Oligonucleotides / administration & dosage
  • Oligonucleotides / chemistry
  • Oligonucleotides / pharmacology*
  • Phosphates / chemistry*
  • PrPSc Proteins / antagonists & inhibitors*
  • PrPSc Proteins / genetics
  • Scrapie / metabolism*
  • Scrapie / prevention & control*
  • Survival

Substances

  • Oligonucleotides
  • Phosphates
  • PrPSc Proteins
  • phosphorodithioic acid