GLYCODRUGS

Glycodrugs: new strategies for controlling the activity of glycosidase enzymes and their application in therapies for lysosomal storage diseases and cancer

Coordinatore	UNIVERSIDAD DE SEVILLA    more  Organization address address: CALLE S. FERNANDO 4 city: SEVILLA postcode: 41004 contact info Titolo: Prof. Nome: Carmen Cognome: Ortiz-Mellet Email: send email Telefono: +34 954 559806 Fax: +34 954 624960
Nazionalità Coordinatore	Spain [ES]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-CIG
Funding Scheme	MC-CIG
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-07-01   -   2017-06-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSIDAD DE SEVILLA  Organization address address: CALLE S. FERNANDO 4 city: SEVILLA postcode: 41004 contact info Titolo: Prof. Nome: Carmen Cognome: Ortiz-Mellet Email: send email Telefono: +34 954 559806 Fax: +34 954 624960	ES (SEVILLA)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'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.'