A novel generation of heparan sulfate mimetics for the treatment of prion diseases

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 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. 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.