NR AOOE
AU Adjou,K.T.; Simoneau,S.; Sales,N.; Lamoury,F.; Dormont,D.; Papy-Garcia,D.; Barritault,D.; Deslys,J.P.; Lasmezas,C.I.
TI A novel generation of heparan sulfate mimetics for the treatment of prion diseases
QU Journal of General Virology 2003 Sep; 84(9): 2595-603
IA http://vir.sgmjournals.org/cgi/content/full/84/9/2595
PT journal article
AB The accumulation of PrPres, the protease-resistant abnormal form of the host-encoded cellular prion protein, PrPc, plays a central role in transmissible spongiform encephalopathies. Human contamination by bovine spongiform encephalopathy (BSE) has propelled many scientific teams on a highway for anti-prion drug development. This study reports that heparan sulfate mimetics (HMs), developed originally for their effect on tissue regeneration, abolish prion propagation in scrapie-infected GT1 cells. PrPres does not reappear for up to 50 days post-treatment. When tested in vivo, one of these compounds, HM2602, hampered PrPres accumulation in scrapie- and BSE-infected mice and prolonged significantly the survival time of 263K scrapie-infected hamsters. Interestingly, HM2602 is an apparently less toxic and more potent inhibitor of PrPres accumulation than dextran sulfate 500, a molecule known to exhibit anti-prion properties in vivo. Kinetics of PrPres disappearance in vitro and unaffected PrPc levels during treatment suggest that HMs are able to block the conversion of PrPc into PrPres. It is speculated that HMs act as competitors of endogenous heparan sulfates known to act as co-receptors for the prion protein. Since these molecules are particularly amenable to drug design, their anti-prion potential could be developed further and optimized for the treatment of prion diseases.
MH Animal; Anti-Infective Agents/chemical synthesis/*pharmacology; Cattle; Cells, Cultured; Disease Models, Animal; Disease Progression; Drug Design; Encephalopathy, Bovine Spongiform/*drug therapy; Female; Hamsters; Heparitin Sulfate/chemical synthesis/*pharmacology; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Molecular Structure; PrPc Proteins/antagonists & inhibitors; PrPsc Proteins/*antagonists & inhibitors; Scrapie/*drug therapy; Support, Non-U.S. Gov't; Time Factors
AD CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
SP englisch
PO England