Rational design of cell active C2-modified DGJ analogues for the inhibition of human α-galactosidase A (GALA)

• Published in: Organic & biomolecular chemistry Vol. 19; no. 37; pp. 857 - 862
• Main Authors: Ashmus, Roger A, Wang, Yang, González-Cuesta, Manuel, King, Dustin T, Tiet, Ben, Gilormini, Pierre-André, García Fernández, José M, Ortiz Mellet, Carmen, Britton, Robert, Vocadlo, David J
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 29.09.2021; Royal Society of Chemistry
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemical synthesis; 1-Deoxynojirimycin - chemistry; 1-Deoxynojirimycin - pharmacology; alpha-Galactosidase - antagonists & inhibitors; alpha-Galactosidase - metabolism; Carbohydrates; Chemistry; Chemistry, Organic; Design modifications; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fabry Disease - drug therapy; Fabry Disease - enzymology; Galactosidase; Glucosamine - analogs & derivatives; Glycosidases; Humans; Molecular Structure; Physical Sciences; Science & Technology; Structure-Activity Relationship; POTENT; PHARMACOLOGICAL CHAPERONES; CLASSIFICATION; FABRY-DISEASE; 1-DEOXYGALACTONOJIRIMYCIN; MOLECULAR-BASIS; BINDING; CHLORINATION; WATER
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d1ob01526e

We report the rational design and synthesis of C2-modified DGJ analogues to improve the selective inhibition of human GALA over other glycosidases. We prepare these analogues using a concise route from non-carbohydrate materials and demonstrate the most selective inhibitor 7c (∼100-fold) can act in Fabry patient cells to drive reductions in levels of the disease-relevant glycolipid Gb3. A selective inhibitor of GALA reduces Gb3 levels by over half within Fabry disease patient fibroblasts.