n-octyl-beta-valienamine and valienamine

This article reviews synthesis and structures of carbaglycosylamines, a group of carbocyclic sugar analogues. Some unsaturated derivatives are known to be potent glycosidase inhibitors. Among them, N-octyl-4-epi-beta-valienamine as a lysosomal beta-galactosidase inhibitor is currently undergoing a new molecular therapeutic trial (chemical chaperone therapy) for control of the human beta-galactosidase deficiency disorder, G(M1)-gangliosidosis.

Topics: Animals; Cyclohexenes; Drug Design; Enzyme Inhibitors; Gangliosidosis, GM1; Glycoside Hydrolases; Hexosamines; Humans; Mice; Molecular Chaperones; Structure-Activity Relationship

GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal β-galactosidase (β-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation. Pharmacological chaperone (PC) therapy is a newly developed molecular therapeutic approach by using small molecule ligands of the mutant enzyme that are able to promote the correct folding and prevent endoplasmic reticulum-associated degradation and promote trafficking to the lysosome. In this report, we describe the enzymological properties of purified recombinant human β-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, β-Gal(R201C) and β-Gal(I51T). We have also evaluated the PC effect of two competitive inhibitors of β-Gal. Moreover, we provide a detailed atomic view of the recognition mechanism of these compounds in comparison with two structurally related analogues. All compounds bind to the active site of β-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues. Moreover, the binding affinity, the enzyme selectivity, and the PC potential are strongly affected by the mono- or bicyclic structure of the core as well as the orientation, nature, and length of the exocyclic substituent. These results provide understanding on the mechanism of action of β-Gal selective chaperoning by newly developed PC compounds.

Topics: 1-Deoxynojirimycin; beta-Galactosidase; Catalytic Domain; Crystallography, X-Ray; Cyclohexenes; Enzyme Inhibitors; Enzyme Stability; Gangliosidosis, GM1; Hexosamines; Humans; Hydrogen Bonding; Hydrogen-Ion Concentration; Imino Sugars; Inositol; Kinetics; Models, Molecular; Molecular Structure; Mucopolysaccharidosis IV; Mutation; Protein Structure, Tertiary; Static Electricity; Structure-Activity Relationship