Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLBâ‚ alleles causing GM1-gangliosidosis and Morquio B disease.

[gm1 gangliosidosis]

Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes , pharmacological chaperones aim at a gain of function of endogenous gene products . Deficits resulting from missense mutations may become treatable by small , competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes . This may prevent their premature degradation and normalize intracellular trafficking as well as biological half -life . A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains . Our previous work on mutations of the Î²-galactosidase (Î²-gal ) gene , causing GM 1 gangliosidosis (GM 1 ) and Morquio B disease (MBD ), respectively , characterized clinical phenotypes as well as biosynthesis , intracellular transport and subcellular localization of mutants . We recently identified an effective chaperone , DL-HexDGJ (Methyl 6 -{[N (2 )-(dansyl )-N (6 )-(1 ,5 -dideoxy-D-galactitol-1 ,5 -diyl )- L-lysyl ]amino } hexanoate ), among a series of N-modified 1 -deoxygalactonojirimycin derivatives carrying a dansyl group in its N-acyl moiety . Using novel and flexible synthetic routes , we now report on the effects of two oligofluoroalkyl-derivatives of 1 -deoxygalactonojirimycin , Ph (TFM )(2 )OHex-DGJ (N-(Î±,Î±-di -trifluoromethyl ) benzyloxyhexyl-1 ,5 -dideoxy-1 ,5 -imino-D : -galactitol ) and (TFM )(3 )OHex-DGJ (N-(Nonafluoro-tert-butyloxy )hexyl-1 ,5 -dideoxy-1 ,5 -imino-D : -galactitol ) on the Î²-gal activity of GM 1 and MBD fibroblasts . Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM 1 fibroblasts with chaperone-sensitive mutations . Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation . The fact that the novel compounds were effective at very low concentrations (0 .5 -10 Î¼M ) in the cell culture medium as well as their novel chemical character suggest future testing in animal models . This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases .

Diseases
Validation

Diseases presenting "intralysosomal maturation" symptom

gm1 gangliosidosis

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