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 inhibition of human beta-galactosidase activity. Among them, 1-deoxy-galactonojirimycin and N-(n-butyl)-deoxy-galactonojirimycin showed an inhibitory effect at high concentrations. However, they restored mutant enzyme activities expressed in enzyme-deficient knockout mouse fibroblasts and human beta-galactosidosis fibroblasts at lower intracellular concentrations. This effect was more remarkable on G(M1)-gangliosidosis mutations (R201C, I51T, R201H, R457Q) than Morquio B disease mutations (W273L, Y83H). These low molecular compounds pass though the blood-brain barrier in mice. We hope that this new therapeutic approach will become clinically applicable in the near future.
Tominaga
L
L
Gene Research Center, Tottori University, 86 Nishimachi, Yonago 683-8503, Japan.
Ogawa
Y
Y
Taniguchi
M
M
Ohno
K
K
Matsuda
J
J
Oshima
A
A
Suzuki
Y
Y
Nanba
E
E
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018076:DNA, Complementary / Q000187:drug effects / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics / Q000378:metabolism; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D009154:Mutation / Q000187:drug effects / Q000502:physiology; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics
D018076:DNA, Complementary; D017485:1-Deoxynojirimycin; C090092:migalastat; D001616:beta-Galactosidase