NR AOVL
AU Larramendy,C.; Barret,A.; Daudigeos,E.; Mathieu,E.; Riffet,C.; Papy-Garcia,D.; Barritault,D.; Lasmezas,C.I.; Deslys,J.P.
TI Promising new drugs for prion therapeutics
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - IV-27
PT Konferenz-Poster
AB
The transmissibility of BSE (Bovine Spongiform Encephalopathy) to man has deeply modified the perception of prion diseases. The future number of patients developing a variant Creutzfeldt-Jakob disease is still uncertain and, given that no effective treatment is presently available, the development of new therapeutic strategies is of crucial importance.
A novel generation of heparan sulfate mimetics has recently been described for the treatment of prion diseases. These drugs, originally developped for their tissue regeneration properties, abolished prion propagation in scrapie-infected GT1 cells and one of these, HM2602, limited PrPres accumulation in scrapie- and BSE-infected mice and significantly prolonged survival time in 263K scrapie-infected hamsters*.
We have studied the anti-prion activities of a new series of HM2602 derivatives. All these compounds, when tested in the scGT1 cell model, hampered PrPres accumulation at doses lower or equal to HM2602. These results allowed us to determine the structural elements responsible for the anti-prion activity.
The two more potent inhibitors, CR29 and CR36, which were chosen for further investigation offer the interest of a better tolerance than the original molecule HM2602 or than pentosan polysulphate (PPS). CR29 and CR36 completely block PrPres accumulation after a single treatment at 1µg/ml and at 10µg/ml respectively. Interestingly, CR36 has a low molecular weight and therefore might be more amenable to crossing the blood-brain barrier. PPS used as a control is not efficient in this scGT1 cell model after a single treatment even at 100µg/ml (however, an effect is observed with repeated treatments at 10µg/ml).
These constitute promising results for the development of Heparan Mimetics as anti-prion drugs.
In vivo assays are underway, in mice infected with the scrapie strain C506 or the BSE strain 6PB1 and the preliminary results will be presented.
*: K.T. Adjou et al., J Gen Virol, 2003
AD C. Larramendy, A. Barret, E. Daudigeos, E. Mathieu, C. Lasmézas, J.P. Deslys, CEA, DSV/DRM, GIDTIP, 18 Route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France; C. Riffet, D. Papy-Garcia, D. Barritault, Laboratoire CRRET, CNRS FRE24-12, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil Cedex, France; D. Papy-Garcia, OTR3 sarl, 33 rue Pierre Brossolette, 94000 Créteil, France
SP englisch
PO Deutschland