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 the inhibition of the key enzyme in GSL biosynthesis, ceramide glucosyltransferase (CGT) 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 glycosphingolipid (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 preclinical status of imino sugars is compared with substrate reduction therapy (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 central nervous system (CNS), and have well-characterized biological and pharmacological properties.

Iminosugar inhibitors for treating the lysosomal glycosphingolipidoses

/pdf/quantitative-regulation-of-nuclear-pore-complex-proteins-by-58yvjl7wm6.pdf

Quantitative Regulation of Nuclear Pore Complex Proteins by O-glcNAcylation

................................................................................................................................. VI LIST OF TABLES ......................................................................................................................... X LIST OF ILLUSTRATIONS ....................................................................................................... XI CHAPTER 1 : INTRODUCTION............................................................................................... 1 Thioamide Properties .................................................................................................................... 2 Thioamides in Nature: Biosynthesis, Structure, and Function ................................................. 6 Closthioamide .............................................................................................................................. 6 YcaO-TfuA-dependent thioamidation ......................................................................................... 10 Thioamide-Containing Protein: Methyl-Coenzyme M Reductase (MCR) .................................. 13 Potential for Other Thioamide Natural Products ........................................................................ 15 Synthetic Thioamide in Peptides and Proteins ......................................................................... 16 Chemical Synthesis of Thioamide-Containing Peptides ............................................................ 17 Uses of Synthetic Thioamide Peptides as Fluorescence Quencher Probes ............................. 20 Synthetic thioamide peptides for other uses .............................................................................. 24 Thioprotein Semisynthesis ......................................................................................................... 32 Thioamide Effects in Full Length Proteins. ................................................................................ 35 Synopsis ....................................................................................................................................... 36 CHAPTER 2 : IMPROVED FMOC DEPROTECTION METHODS FOR THE SYNTHESIS OF THIOAMIDE-CONTAINING PEPTIDES................................................. 38 2.

/pdf/development-of-thioamides-as-protein-probes-4fjurv2qaq.pdf

Development Of Thioamides As Protein Probes

Screening a natural compound library led to the identification of resorufin as a highly selective and potent inhibitor of protein kinase CK2. Out of 52 kinases tested, only CK2 was inhibited, in contrast to emodin, a structurally related, known CK2 inhibitor that, in addition to CK2, inhibited ten other kinases by 90%. The IC50 values determined for the CK2 holoenzymes were 1.5 mol/l and for the free catalytic subunits ca. 4 mol/l. Altogether four cell lines were subjected to resorufin and emodin treatment. In the case of the three prostate carcinoma cell lines (PC-3, DU-145, LNCaP), 24 h treatment with 40 mol/l resorufin led to 15–20% dead cells; however, no caspase-mediated apoptosis was observed. In the case of the colorectal carcinoma HCT116 cell line, a similar picture was obtained, yet, when resorufin was administered to cells treated with doxorubicin, apoptosis was strongly induced within 24 h. Endogenous protein kinase CK2 was inhibited by resorufin by ca. 80% in the three prostate cell lines. In the case of the HCT116 cells, the inhibition was only 40% supporting the notion of cell line-specific selectivity. Moreover, we analysed the effect of resorufin and emodin on selected signalling molecules in the cell lines under investigation.

Resorufin - a lead for a new protein kinase CK2 inhibitor

Development of chemical tools for studying human O-GlcNAcase activity

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Development of chemical tools for studying human O-GlcNAcase activity