NR AUIA
AU Kocisko,D.A.; Vaillant,A.; Lee,K.S.; Arnold,K.M.; Bertholet,N.; Race,R.E.; Olsen,E.A.; Juteau,J.M.; Caughey,B.W.
TI Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides
QU Antimicrobial Agents and Chemotherapy 2006 Mar; 50(3): 1034-44
PT journal article
AB 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.
MH Animals; Base Composition; Cell Line; Comparative Study; Cricetinae; Hydrophobicity; Inhibitory Concentration 50; Injections, Intraperitoneal; Injections, Subcutaneous; Mice; Mice, Transgenic; Molecular Weight; Nucleic Acid Conformation; Oligonucleotides/administration & dosage/chemistry/*pharmacology; Phosphates/*chemistry; PrPsc Proteins/*antagonists & inhibitors/genetics; Research Support, N.I.H., Intramural; Research Support, U.S. Gov't, Non-P.H.S.; Scrapie/*metabolism/*prevention & control; Survival
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
SP englisch
PO USA