NR AXTZ
AU Ouidja,M.O.; Petit,E.; Kerros,M.E.; Ikeda,Y.; Brugere-Picoux,J.; Deslys,J.P.; Barritault,D.; Adjou,K.T.; Papy-Garcia,D.
TI Structure-Activitiy Relationship of Heparan Mimetics: New Outlines for the Modeling of Novel Anti-Prion Drugs Candidates
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.71
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB Prion diseases are long invariable fatal diseases for which a great number of therapeutics have been tested. Heparan mimetics (HM) are a family of polysulfated molecules that includes HM2602 and HM-CR36 that together with pentosan polysulfate, have been reported among the more efficient drugs used in experimental models of prion diseases. These sulfated polyanions are presumed to act as competitors of the heparan sulfates, natural co-receptors for PrP on the cell surface. The poly-alcoholic backbone of HM offers a wide range of substitution possibilities. Here, we report the syntheses of a library of HM of different molecular sizes, containing various sulfation and carboxylation levels, and bearing or not hydrophobic core substitutions. We report the first study regarding the relationship between these structural features and the compounds capacities to bind to PrPc and PrPsc in an ELISA type test, and to inhibit the replication of PrPsc in chronically infected cells (ScGT1-7). ED50 determinations and effect comparisons at fixed doses in both models shown that i) molecules with a moderate sulfation level (substitution degree from 1 to 1.2) were more active than the highly sulfated (substitution degree superior to 1.4) and than the poorly sulfated (substitution degree < 1) ones, ii) that the presence of carboxylic groups decreases compounds efficacities, and that iii) the presence of hydrophobic moieties improves anti-PrP activities even for the poorly sulfated products. Among the tested hydrophobic cores, the phenylalanine methylester amide functionality showed the best activity, followed by the ethylhexylamide and the noctylamide. The importance of all these factors including their type of interactions with PrPc and PrPres will be discussed.
AD M.O. Ouidja, Ecole Nationale Veterinaire D'Alfort/Cea, France; E. Petit, M.E. Kerros, Y. Ikeda, D. Barritault, D. Papy-Garcia, Universite Paris Xii, France; J. Brugere-Picoux, K. Adjou, Ecole Nationale Veterinaire D'Alfort, France; J.P. Deslys, CEA, France
SP englisch
PO Schottland
EA pdf-Datei und Poster (Posterautoren: M.O. Ouidja, E. Petit, Y. Ikeda, D. Singabraya, J.P. Deslys, J. Brugere-Picoux, K.T. Adjou und D. Papy-Garcia; Postertitel: Structure-activity studies of heparan mimetic polyanions for anti-prion therapies)