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Antimicrobial Agents and Chemotherapy, March 2006, p. 1034-1044, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.1034-1044.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Potent Antiscrapie Activities of Degenerate Phosphorothioate Oligonucleotides

David A. Kocisko,1,{dagger} Andrew Vaillant,2,{dagger} Kil Sun Lee,1 Kevin M. Arnold,1 Nadine Bertholet,2 Richard E. Race,1 Emily A. Olsen,1 Jean-Marc Juteau,2* and Byron Caughey1*

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana,1 REPLICor Inc., Laval, Quebec, Canada2

Received 30 August 2005/ Returned for modification 14 November 2005/ Accepted 8 December 2005

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.

* Corresponding author. Mailing address for Jean-Marc Juteau: REPLICor Inc., Laval, Quebec, Canada H7V 5B7. Phone: (450) 688-6068. Fax: (450) 688-3158. E-mail: jmjuteau{at}replicor.com. Mailing address for Byron Caughey: NIH, Rocky Mountain Laboratories, 903 S. 4th Street, Hamilton, MT 59840. Phone: (406) 363-9264. Fax: (406) 363-9286. E-mail: bcaughey{at}niaid.nih.gov.

{dagger} These authors contributed equally to this work.

Antimicrobial Agents and Chemotherapy, March 2006, p. 1034-1044, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.1034-1044.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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