Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides.
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.
Kocisko
David A
DA
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Vaillant
Andrew
A
Lee
Kil Sun
KS
Arnold
Kevin M
KM
Bertholet
Nadine
N
Race
Richard E
RE
Olsen
Emily A
EA
Juteau
Jean-Marc
JM
Caughey
Byron
B
D000818:Animals; D001482:Base Composition; D002460:Cell Line; D006224:Cricetinae; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010710:Phosphates / Q000737:chemistry*; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012608:Scrapie / Q000378:metabolism* / Q000517:prevention & control*; D013534:Survival
D009841:Oligonucleotides; D010710:Phosphates; D018620:PrPSc Proteins; C083120:phosphorodithioic acid