Imino Sugar Inhibitors for Treating the Lysosomal Glycosphingolipidoses.

Glycobiology. 2005 May 18; [Epub ahead of print]

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Butters TD, Dwek RA, Platt FM.

Oxford Glycobiology Institute, Department of Biochemistry University of Oxford, South Parks Road Oxford OX1 3QU UK.

The inherited metabolic disorders of glycosphingolipid (GSL) metabolism are a relatively rare group of diseases that have diverse and often neurodegenerative phenotypes. Typically, a deficiency in catabolic enzyme activity leads to lysosomal storage of GSL substrates and in many diseases, several other glycoconjugates. A novel generic approach to treating these diseases has been termed substrate reduction therapy (SRT) and the discovery and development of N-alkylated imino sugars as effective and approved drugs is discussed. An understanding of the molecular mechanism for inhibition of the key enzyme in GSL biosynthesis, ceramide glucosyltransferase by N-alkylated imino sugars has also lead to compound design for improvements to inhibitory potency, bioavailability, enzyme selectivity and biological safety. Following a successful clinical evaluation of one compound, N-butyl-deoxynojirimycin; NB-DNJ; miglustat; Zavesca, for treating type I Gaucher disease, issues regarding the significance of side effects and CNS access have been addressed as exposure of drug to patients has increased. An alternative experimental approach to treat specific GSL lysosomal storage diseases is to use imino sugars as molecular chaperons that assist protein folding and stability of mutant enzymes. The principles of chaperon-mediated therapy (CMT) are described and the potential efficacy and pre-clinical status of imino sugars is compared to SRT. The increasing use of imino sugars for clinical evaluation of a group of storage diseases that are complex and often intractable disorders to treat has considerable benefit. This is particularly so given the ability of small molecules to be orally available, penetrate the CNS and have well characterised biological and pharmacological properties.

PMID: 15901676 [PubMed - as supplied by publisher]

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