A novel generation of heparan sulfate mimetics for the treatment of prion diseases.
The accumulation of PrP(res), the protease-resistant abnormal form of the host-encoded cellular prion protein, PrP(C), 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. PrP(res) does not reappear for up to 50 days post-treatment. When tested in vivo, one of these compounds, HM2602, hampered PrP(res) 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 PrP(res) accumulation than dextran sulfate 500, a molecule known to exhibit anti-prion properties in vivo. Kinetics of PrP(res) disappearance in vitro and unaffected PrP(C) levels during treatment suggest that HMs are able to block the conversion of PrP(C) into PrP(res). 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.
Adjou
Karim Tarik
KT
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
Simoneau
Steve
S
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
Salès
Nicole
N
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
Lamoury
François
F
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
Dormont
Dominique
D
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
Papy-Garcia
Dulce
D
OTR3 Sarl, 33 rue Pierre Brossolette, 94000 Créteil, France.
Barritault
Denis
D
Laboratoire CRETT, CNRS FRE2412, Université Paris XII-Val de Marne, avenue du Général de Gaulle, 94010 Créteil Cedex, France.
Deslys
Jean-Philippe
JP
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
Lasmézas
Corinne Ida
CI
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D006224:Cricetinae; D004195:Disease Models, Animal; D018450:Disease Progression; D015195:Drug Design; D016643:Encephalopathy, Bovine Spongiform / Q000188:drug therapy*; D005260:Female; D006497:Heparan Sulfate / Q000138:chemical synthesis / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018621:PrPC Proteins / Q000037:antagonists & inhibitors; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors*; D012608:Scrapie / Q000188:drug therapy*; D013997:Time Factors
D000890:Anti-Infective Agents; D006497:Heparan Sulfate; D018621:PrPC Proteins; D018620:PrPSc Proteins