dc.creator | Sánchez Fernández, Elena Matilde | es |
dc.creator | García Fernández, José Manuel | es |
dc.creator | Ortiz Mellet, Carmen | es |
dc.date.accessioned | 2022-05-27T10:11:16Z | |
dc.date.available | 2022-05-27T10:11:16Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | Sánchez Fernández, E.M., García Fernández, J.M. y Ortiz Mellet, C. (2016). Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases. Chemical Communications, 52 (497), 5497-5515. | |
dc.identifier.issn | 1359-7345 | es |
dc.identifier.issn | 1364-548X | es |
dc.identifier.uri | https://hdl.handle.net/11441/133800 | |
dc.description.abstract | Lysosomal storage disorders (LSDs) are often caused by mutations that destabilize native folding and
impair the trafficking of enzymes, leading to premature endoplasmic reticulum (ER)-associated degradation,
deficiencies of specific hydrolytic functions and aberrant storage of metabolites in the lysosomes.
Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are available for a few of these
conditions, but most remain orphan. A main difficulty is that virtually all LSDs involve neurological
decline and neither proteins nor the current SRT drugs can cross the blood–brain barrier. Twenty years
ago a new therapeutic paradigm better suited for neuropathic LSDs was launched, namely pharmacological chaperone (PC) therapy. PCs are small molecules capable of binding to the mutant protein at the
ER, inducing proper folding, restoring trafficking and increasing enzyme activity and substrate processing
in the lysosome. In many LSDs the mutated protein is a glycosidase and the accumulated substrate is
an oligo- or polysaccharide or a glycoconjugate, e.g. a glycosphingolipid. Although it might appear
counterintuitive, substrate analogues (glycomimetics) behaving as competitive glycosidase inhibitors are
good candidates to perform PC tasks. The advancements in the knowledge of the molecular basis of
LSDs, including enzyme structures, binding modes, trafficking pathways and substrate processing
mechanisms, have been put forward to optimize PC selectivity and efficacy. Moreover, the chemical versatility
of glycomimetics and the variety of structures at hand allow simultaneous optimization of chaperone and
pharmacokinetic properties. In this Feature Article we review the advancements made in this field in the last
few years and the future outlook through the lessons taught by three archetypical LSDs: Gaucher disease,
GM1-gangliosidosis and Fabry disease | es |
dc.description.sponsorship | Ministerio de Economía y Competitividad de España (MINECO). SAF2013-44021-R y CTQ2015-64425-C2-1-R | es |
dc.description.sponsorship | Junta de Andalucía. FQM-1467 | es |
dc.description.sponsorship | Seventh Framework Programme de la Unión Europea. FP7-People2012-CIG | es |
dc.format | application/pdf | es |
dc.format.extent | 19 p. | es |
dc.language.iso | eng | es |
dc.publisher | Royal Society of Chemistry | es |
dc.relation.ispartof | Chemical Communications, 52 (497), 5497-5515. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.title | Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases | es |
dc.type | info:eu-repo/semantics/article | es |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Química orgánica | es |
dc.relation.projectID | SAF2013-44021-R | es |
dc.relation.projectID | CTQ2015-64425-C2-1-R | es |
dc.relation.projectID | FQM-1467 | es |
dc.relation.projectID | FP7-People2012-CIG | es |
dc.relation.publisherversion | https://doi.org/10.1039/C6CC01564F | es |
dc.identifier.doi | 10.1039/C6CC01564F | es |
dc.journaltitle | Chemical Communications | es |
dc.publication.volumen | 52 | es |
dc.publication.issue | 497 | es |
dc.publication.initialPage | 5497 | es |
dc.publication.endPage | 5515 | es |
dc.identifier.sisius | 20918605 | es |
dc.contributor.funder | Ministerio de Economía y Competitividad (MINECO). España | es |
dc.contributor.funder | Junta de Andalucía | es |
dc.contributor.funder | Universidad de Sevilla | es |
dc.contributor.funder | European Union (UE). FP7 | es |
dc.contributor.funder | European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) | es |