Structure-activity studies of heparan mimetic polyanions for anti-prion therapies.
Polysulfated molecules, as the family of heparan mimetics (HMs) and pentosan polysulfate, are considered among the more promising drugs used in experimental models of prion diseases. Regardless of their therapeutic potential, structure-function studies on these polyanions are still missing. Here, we report the syntheses of a library of HMs of different molecular sizes, containing various sulfation and carboxylation levels, and substituted or not by different hydrophobic cores. The HMs capacities to inhibit the accumulation of PrPres in chronically infected cells (ScGT1-7) and their PrPc binding abilities were examined. Our results showed that an optimal size and sulfation degree are needed for optimum activity, that incorporation of hydrophobic moieties increases compounds efficacy and that the presence of carboxymethyl moieties decreases it. These structural features should be considered on the modelling of polyanionic compounds for optimum anti-prion activities and for advancing in the understanding the mechanisms involved in their biological actions.
Ouidja
Mohand-Ouidir
MO
Laboratoire CRRET CNRS-UMR 7149, Université Paris 12, 94010 Créteil, France.
Petit
Emmanuel
E
Kerros
Marie-Emmanuelle
ME
Ikeda
Yasunori
Y
Morin
Christophe
C
Carpentier
Gilles
G
Barritault
Denis
D
Brugère-Picoux
Jeanne
J
Deslys
Jean-Philippe
JP
Adjou
Karim
K
Papy-Garcia
Dulce
D
D000818:Animals; D000838:Anions; D001665:Binding Sites; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000627:therapeutic use; D002460:Cell Line; D006497:Heparan Sulfate / Q000008:administration & dosage* / Q000737:chemistry*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship