Chemical Biology of Neurodegenerative Diseases

The Chemical Biology Group investigates key biological processes by means of tailored organic molecules synthesised in the laboratory. The substances can be used for the study of normal but also pathological cellular functions in the neurosciences.

Modulation of Protein-Protein Interactions

Protein-protein interactions are the basis of many cellular processes. Modulation of these interactions is one of the most complicated and at the same time most relevant processes in medicinal chemistry. It is becoming increasingly clear that many diseases result from misregulation of protein-protein interactions (cancer, neurodegenerative diseases, viral infections, etc.). Molecules that modulate these interactions offer the possibility to inhibit disturbed interactions or restore the native function of proteins.
The aggregation of unfolded proteins (β-amyloid and tau) is underlying neurodegenerative diseases (Alzheimer’s disease, tauopathies) characterised by neuronal loss and synaptic abnormalities leading to severe impairment of cognitive abilities.⁽¹⁾ We started to identify inhibitors of those protein-protein interactions and to determine structure-activity relation of the compounds. Moreover, we design novel generations of inhibitors that also target peptide oligomers.
Furthermore, the development of novel screening methods for the identification of inhibitors of other disease-relevant protein-protein interactions is expected to lead to the discovery of new drugs. 

Modulation of γ-Secretase Activity

The selective inhibition of proteases that cleave the aggregation-prone peptides involved in Alzheimer´s disease is one approach to prevent or ameliorate the disease. However, because γ-secretase has multiple substrates, full inhibition causes severe side effects. Notwithstanding, it has been reported that a subset of non-steroidal anti-inflammatory drugs (NSAIDs) affect γ-secretase activity thereby allowing specific inhibition of the amyloidogenic Aβ-42 production⁽²⁾.
We have established a structure-activity relation using a combinatorial library of NSAIDs; this allows to develop improved modulators as therapeutic substances and chemical probes.⁽³⁾ Furthermore, the chemical toolkit allows the study of crucial physiological aspects of the γ-secretase, such as its selectivity and mechanism of regulation.

Molecular Probes

An elegant tool to study and interfere with cellular signalling, both spatially and temporally, are photolabile organic molecules. We design and synthesise various chemical probes to study for example chemotaxis⁽⁴⁾ and inflammation. Furthermore, new methods for in vivo labelling and activation of biomolecules are developed.

References:

[1] Bulic B. et al. (2009) "Development of tau aggregation inhibitors for Alzheimer's disease" Angew. Chem. Int. Ed. Engl. 48. 1740-1752

[2] Weggen, S. et al. (2001) "A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity" Nature 414, 212-216  

[3] http://www.knd-demenzen.de/KNDD/English/NSAIDs+consortium?sid=V1mme3xaj0bGFiEeSmugr0&iid=1

[4] Kaupp, U.B. et al. (2003) "The signal flow and motor response controlling chemotaxis of sea urchin sperm" Nature Cell Biology 5, 109-117