Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity : Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine
| Autor: | Michael Schalli, Seyed A. Nasseri, Werner Windischhofer, Ana Torvisco, Christina Tysoe, Wendy A. Offen, Stephen G. Withers, Patrick Weber, Philipp Müller, Marion Tschernutter, Summer Averill, Eduard Paschke, Andreas Wolfsgruber, Martin Thonhofer, Bettina M. Pabst, Arnold E. Stütz, Tanja M. Wrodnigg, Gideon J. Davies, Andrés G. Santana |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Molecular Conformation
Pharmaceutical Science 4-epi-isofagomine Ligands 01 natural sciences Analytical Chemistry Morquio-B Disease Drug Discovery GM1-gangliosidosis Moiety Glycoside hydrolase Enzyme Inhibitors 0303 health sciences Chemistry Human cell aminocyclopentane Galactosidases Pharmacological chaperone Biochemistry galactosidase inhibitor Chemistry (miscellaneous) Molecular Medicine Crystallization Imino Pyranoses medicine.drug carbasugar Cyclopentanes Article lcsh:QD241-441 03 medical and health sciences lcsh:Organic chemistry medicine iminoalditol Humans Physical and Theoretical Chemistry Deoxygenation 030304 developmental biology 010405 organic chemistry Organic Chemistry Galactosidase activity 0104 chemical sciences pharmacological chaperone Mutant Proteins Lysosomes Molecular Chaperones |
| Zdroj: | Molecules Molecules, Vol 25, Iss 4025, p 4025 (2020) Volume 25 Issue 17 |
| ISSN: | 1420-3049 |
| Popis: | Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid &beta galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent &beta d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a &ldquo strategic&rdquo hydroxyl group. New compounds have revealed highly promising activities with a range of &beta galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease. |
| Databáze: | OpenAIRE |
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