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1 CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France
2 OTR3 Sarl, 33 rue Pierre Brossolette, 94000 Créteil, France
3 Laboratoire CRETT, CNRS FRE2412, Université Paris XII-Val de Marne, avenue du Général de Gaulle, 94010 Créteil Cedex, France
Correspondence
Corinne Ida Lasmézas
lasmezas{at}cea.fr
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.
Published ahead of print on 11 June 2003 as DOI 10.1099/vir.0.19073-0
Present address: Ecole Nationale Vétérinaire d'Alfort, 7 avenue du Général de Gaulle, 94704 Maisons-Alfort, Cedex, France.
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