NR AWLM
AU Ouidja,M.O.; Mouthon,F.; Petit,E.; Papy-Garcia,D.; Carpentier,G.; Deslys,J.P.; Brugere-Picoux,J.; Adjou,K.T.
TI New heparan sulfate mimetics for the treatment of prion diseases: a first structure-activity in vitro study
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions THE-11
PT Konferenz-Poster
AB Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative disorders with long incubation periods such as Creutzfeldt-Jakob disease in man. TSEs are characterized by the accumulation in the brain of an abnormal isoform (PrPres) of the host encoded prion protein (PrPc), which is partially resistant to proteolysis. PrPres, is the only specific marker of the infection, and the inhibition of its accumulation is often used to evaluate the efficacy of therapeutic drugs. There are currently no effective therapies for TSEs. Thus, the development of new therapeutics in human TSEs is of crucial importance. One class of molecules that has shown limited but significant efficiency in the treatment of TSEs is sulfated polyanions such as Pentosan polysulfate and Dextran sulfate 500. However their use is limited by their toxicity. Heparan sulfate bind PrP and play an active role in the PrP catabolic pathway. For this reasons, we thought that new heparan sulfate mimetics (HMs) initially developed for their ability to stimulate tissue repair, would represent good candidates for the development of a PrP-targeted therapeutic against prion diseases. Here, we report the first structure-activity study concerning the relationship between the antiprion activity of HMs and their degree of sulfation, their molecular size, and the influence of different hydrophobic cores. In order to do that, we tested in a cellular model chronically infected with Chandler scrapie strain (ScGT1-7), the ability of a battery of molecules on their capacity to inhibit PrPres formation. Our data show that optimal antiprion activity of sulfated polysaccharides can be reached with medially sulfated molecules. This activity can readily be enhanced by introducing hydrophobic moieties (phenylalanine derivatives and ethylhexylamine) and by reducing molecular size. In conclusion, this novel generation of HMs with low molecular weight and hydrophobic functionalities open new insights for prion therapeutics.
AD M.O. Ouidja: Ecole Nationale Vétérinaire d'Alfort, Laboratoire de pathologie du bétail, Maisons-Alfort, France, and CEA, DSV/DRM/ GIDTIP, Fontenay-aux-Roses, France; F. Mouthon, J.-P. Deslys: CEA, DSV/DRM/ GIDTIP, Fontenay-aux-Roses, France; E. Petit, D. Papy-Garcia, G. Carpentier: Laboratoire CRETT CNRS UMR 7149, Université Paris XIIVal de Marne, Créteil,France; J. Brugère-Picoux, K.T. Adjou: Ecole Nationale Vétérinaire d'Alfort, Laboratoire de pathologie du bétail, Maisons-Alfort, France
SP englisch
PO Italien