Skip Navigation



Glycobiology Advance Access published online on May 18, 2005
Glycobiology, doi:10.1093/glycob/cwi076
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
15/10/43R    most recent
cwi076v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Butters, T. D.
Right arrow Articles by Platt, F. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Butters, T. D.
Right arrow Articles by Platt, F. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received April 27, 2005
Revised May 10, 2005
Accepted May 10, 2005

Article

Imino Sugar Inhibitors for Treating the Lysosomal Glycosphingolipidoses

Terry D. Butters 1*, Raymond A. Dwek 1, and Frances M. Platt 1

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

* To whom correspondence should be addressed.
Terry D. Butters, E-mail: terry.butters{at}bioch.ox.ac.uk


  Abstract

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.

Keywords: glycosphingolipid, lysosomal storage diseases, Gaucher disease, novel therapeutics, enzyme inhibitor.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
B. Lubamba, J. Lebacq, P. Lebecque, R. Vanbever, A. Leonard, P. Wallemacq, and T. Leal
Airway Delivery of Low-Dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice
Am. J. Respir. Crit. Care Med., June 1, 2009; 179(11): 1022 - 1028.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
B. Islam, S. N. Khan, I. Haque, M. Alam, M. Mushfiq, and A. U. Khan
Novel anti-adherence activity of mulberry leaves: inhibition of Streptococcus mutans biofilm by 1-deoxynojirimycin isolated from Morus alba
J. Antimicrob. Chemother., October 1, 2008; 62(4): 751 - 757.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
A. K. Simon, T. Newsom-Davis, M. E. F. Frayne, P. F.-T. Ch'en, A. J. McMichael, and G. R. Screaton
Generation of tumour-rejecting anti-carbohydrate monoclonal antibodies using melanoma modified with Fas ligand
Int. Immunol., April 1, 2008; 20(4): 525 - 534.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Brumshtein, H. M. Greenblatt, T. D. Butters, Y. Shaaltiel, D. Aviezer, I. Silman, A. H. Futerman, and J. L. Sussman
Crystal Structures of Complexes of N-Butyl- and N-Nonyl-Deoxynojirimycin Bound to Acid beta-Glucosidase: INSIGHTS INTO THE MECHANISM OF CHEMICAL CHAPERONE ACTION IN GAUCHER DISEASE
J. Biol. Chem., September 28, 2007; 282(39): 29052 - 29058.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
W. Zheng, J. Padia, D. J. Urban, A. Jadhav, O. Goker-Alpan, A. Simeonov, E. Goldin, D. Auld, M. E. LaMarca, J. Inglese, et al.
Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease
PNAS, August 7, 2007; 104(32): 13192 - 13197.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
H. Zhao, M. Przybylska, I-H. Wu, J. Zhang, C. Siegel, S. Komarnitsky, N. S. Yew, and S. H. Cheng
Inhibiting Glycosphingolipid Synthesis Improves Glycemic Control and Insulin Sensitivity in Animal Models of Type 2 Diabetes
Diabetes, May 1, 2007; 56(5): 1210 - 1218.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
E. Parkinson-Lawrence, M. Fuller, J. J. Hopwood, P. J. Meikle, and D. A. Brooks
Immunochemistry of Lysosomal Storage Disorders
Clin. Chem., September 1, 2006; 52(9): 1660 - 1668.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.