RESUMO
Biomimetic nanoparticles prepared by self-assembly of iminosugar-based glycopolypeptides evidenced remarkable multivalency properties when inhibiting α-mannosidase activity. This approach paves the way to obtain biologically active drug delivery systems having glycosidase inhibition potency.
Assuntos
1-Desoxinojirimicina/química , Glicopeptídeos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Nanopartículas/química , Peptídeos/química , 1-Desoxinojirimicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Glicoproteínas/química , Ligantes , MicelasRESUMO
A series of 18 mono- to 14-valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of ß-glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected iminosugar cluster has been obtained with a tetravalent 1-deoxynojirimycin (DNJ) analogue (3.3-fold increase at 10 µM). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0-fold instead of 2.4-fold) at a cellular concentration (1 µM) reduced by one order of magnitude.
