GLYCODRUGSProject reference: 333594
Funded under :
Glycodrugs: new strategies for controlling the activity of glycosidase enzymes and their application in therapies for lysosomal storage diseases and cancer
Total cost:EUR 100 000
EU contribution:EUR 100 000
Call for proposal:FP7-PEOPLE-2012-CIGSee other projects for this call
Funding scheme:MC-CIG - Support for training and career development of researcher (CIG)
"This project aims to new strategies for the preparation of glycomimetics specifically designed to regulate the activity of enzymes involved in pathological processes (glycodrugs). We will focus on the design of glycomimetics to modulate the activity of glycosidases. Particular emphasis will be placed at developing diversity-oriented synthetic strategies to optimize specificity.
The target applications are two: elaboration of chemical chaperones for the treatment of lysosomal storage disorders (LSDs; Gaucher disease, Fabry disease and gangliosidosis GM1), and the development of compounds with antiproliferative activity in breast cancer.
Compounds able to establish specific interactions with regions of lysosomal glycosidases (beta-glucocerebrosidase and alpha- and beta-galactosidases) surrounding the active site will be designed by incorporating substituents with well-defined orientation. In addition, pH-sensitive elements that will allow an effective bond to the enzyme in the endoplasmic reticulum (ER) will be inserted, forcing the correct folding and providing the traffic to the Golgi apparatus, and at the same time the dissociation of the enzyme:chaperone complex in the lysosome, and thus favouring the rescue of the mutant proteins that cause the disease and the processing of the substrate. Molecular vehicles will also be developed for the directed transport of these chaperones to cells particularly affected in patients with LSDs. For biodistribution studies, labelled derivatives with fluorescent probes will be prepared.
The ability to control the specificity of action by incorporating pseudoaglyconic substituents in bicyclic skeletons sp2-iminosugar-type, also allows the design of specific inhibitors for alpha-glucosidases (ER) or for alpha-mannosidases (Golgi). These enzymes are involved in the aberrant glycosylation of N-glycoproteins in tumor cells, so that its control represents a therapeutic strategy against cancer."
EU contribution: EUR 100 000
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