Galactonojirimycin derivatives restore mutant human beta-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse

Ten low molecular compounds analogous to galactose were screened for inhibi tion of human beta -galactosidase activity. Among them, 1-deoxy-galactonoji rmycin and N-(n-butyl)-deoxy-galactonojirmycin showed an inhibitory effect at high concentrations. However, they restored mutant enzyme activities exp ressed in enzyme-deficient knockout mouse fibroblasts and human beta -galac tosidosis fibroblasts at lower intracellular concentrations. This effect wa s more remarkable on G(M1)-gangliosidosis mutations (R201C, 151T, R201H, R4 57Q) than Morquio B disease mutations (W273L, Y83H). These low molecular co mpounds pass though the blood-brain barrier in mice. We hope that this new therapeutic approach will become clinically applicable in the near future. (C) 2001 Elsevier Science B.V. All rights reserved.