Chemical Chaperones for an experimental therapy of Niemann-Pick Disease Investigations in a New Strategy for a Pharmacological Treatment of an Inborn Metabolic Disorder

A proper folding of proteins is indispensable for their biological function and often is achieved with the help of so-called molecular chaperones. The latter are often also able to stabilize proteins under situations of cellular stress. Chemical chaperones are synthetic small molecules, which can exhibit similar functions to specific target proteins. Such molecules have raised vivid attention in connection with lysosomal storage disorders. Lysosomal storage disorders result from genetic defects on the genes of lysosomal lipid hydrolases leading to drastically reduced enzyme activities and to storage of the lipid subtrates in the lysosomes of various tissues. Reduced enzyme activity is often a result of protein misfolding right after synthesis. In cell culture and in humans, chemical chaperones have been shown to be effective in stabilizing various variant lipid hydrolases, in stimulating their transport to the lysosomes and in increasing lysosomal enzyme activity. Such molecules are under development as medicines for the treatment of various congenital metabolic disorders. A rational approach to chemical chaperones is the synthesis of substrate-analogues or competitive inhibitors. Such molecules will bind to the active site of an enzyme and are able to stabilize the active-site domains of respective variants. The intention of our work is to develop chemical chaperones for acid sphingomyelinase, an enzyme deficient in Niemann-Pick Disease (NPD). It is planned to synthesize molecules suitable as potential chaperones and to conduct functional studies in cells derived from NPD-patients. Many aspects of chemical chaperone action are still unclear. NMR studies of variant and wildtype sphingomyelinase are supposed to provide a deeper understanding of the molecular mechanisms of chemical chaperone action. Moreover, we want to biophysically examine the SAP domain of acid sphingomyelinase for the first time. This may provide a rationale to develop chemical chaperones tailored to stabilize a sphingomyelinase domain other than the active-site domain. The proposed project aims to study and to manipulate the conformation of bio-molecules. Chemical synthesis, functional studies and biophysical methods are complementary employed in order to demonstrate possibilities to treat an inherited metabolic disease. Thus, we are confident that our project perfectly fits into the framework of the initiative -Interplay of molecular conformation and biological function.

Principal Investigators
Arenz, Christoph Prof. Dr. (Details) (Organic Synthesis)

Financer
Volkswagen-Stiftung (VW)

Duration of Project
Start date: 08/2007
End date: 07/2010

Last updated on 2020-09-03 at 17:03