Prions and transmissible spongiform encephalopathy (TSE) chemotherapeutics: A common mechanism for anti-TSE compounds?
No validated treatments exist for transmissible spongiform encephalopathies (TSEs or prion diseases) in humans or livestock. The search for TSE therapeutics is complicated by persistent uncertainties about the nature of mammalian prions and their pathogenic mechanisms. In pursuit of anti-TSE drugs, we and others have focused primarily on blocking conversion of normal prion protein, PrP(C), to the TSE-associated isoform, PrP(Sc). Recently developed high-throughput screens have hastened the identification of new inhibitors with strong in vivo anti-TSE activities such as porphyrins, phthalocyanines, and phosphorthioated oligonucleotides. New routes of administration have enhanced beneficial effects against established brain infections. Several different classes of TSE inhibitors share structural similarities, compete for the same site(s) on PrP(C), and induce the clustering and internalization of PrP(C) from the cell surface. These activities may represent a common mechanism of action for these anti-TSE compounds.
Caughey
B
B
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana 59840, USA. bcaughey@nih.gov
Caughey
W S
WS
Kocisko
D A
DA
Lee
K S
KS
Silveira
J R
JR
Morrey
J D
JD
D000818:Animals; D001665:Binding Sites; D002490:Central Nervous System / Q000473:pathology; D017096:Prion Diseases / Q000188:drug therapy* / Q000517:prevention & control; D011328:Prions / Q000378:metabolism; D013329:Structure-Activity Relationship
D011328:Prions