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Chapter 6

Pharmacological Chaperones to Correct Enzyme Folding, Cellular Trafficking and Lysosomal Activity

A variety of unwanted cellular waste materials and macromolecules (e.g. glycosphingolipids, oligosaccharides, glycoproteins, glycogen, peptides, cholesterol, etc.) are enzymatically degraded in a cellular organelle known as the lysosome, with the resulting products recycled into various biosynthetic pathways. Genetic defects that reduce the activity for any one of the enzymes that are responsible for these processes can result in accumulation of one or more substrates, compromised cellular function, and disease pathology. Over the last 10 to 20 years there have been significant advances in understanding the basic biochemistry and cell biology that underlie these diseases, which are known collectively as lysosomal storage diseases (LSDs). In turn, this has led to several treatment options, where virtually none had previously existed. A relatively new and promising therapeutic approach involves pharmacological chaperones (PCs), small molecules that are designed to bind and stabilise mutant lysosomal enzymes, and to improve trafficking to their proper cellular destination, the lysosome, where increased activity can aid in the clearance of storage material. This chapter will outline the mechanism of action of PCs, and describe how such molecules are identified and characterised pre-clinically using biochemical and cell-based assays, as well as animal models of LSDs.

Publication details

Print publication date
14 Aug 2014
Copyright year
Print ISBN
ePub eISBN

From the book series:
Drug Discovery