Klaus Bertram Nissen

September 2004 - July 2007: 
BSc (Pharm), Faculty of Pharmaceutical Sciences, University of Copenhagen

September 2007 – February 2010:
MSc (Pharm), Faculty of Pharmaceutical Sciences, University of Copenhagen

February 2009 – December 2009:
MSc Student, Institute for Molecular Biosciences, University of Queensland, Australia

Novel inhibitors of neuronal protein-protein interactions

Background
The family of ionotropic glutamate (iGlu) receptors are crucial for normal brain function such as memory formation. Dysfunction of iGlu receptors is involved in a range of neurological and psychiatric diseases; and iGlu receptors are considered important targets for diseases such as Alzheimer’s disease, brain damage following ischemia and schizophrenia.

Perturbing iGlu receptors is therefore a promising strategy for treating neurodegenerative diseases, but finding the appropriate balance between reducing harmful effects while keeping physiological functions intact is very difficult. In recent years it has become apparent that iGlu receptors are organized into multi-protein signalling complexes with a complex network of intracellular proteins and that these interactions play essential roles for the functions of iGlu receptors. This has lead to the conceptually novel idea of modulation of protein-protein interactions (PPIs) between iGlu receptors and their intracellular protein partners as approach to the treatment of diseases in the brain.

Currently, more than 40 unique proteins have been identified that bind to iGlu receptors, and for the vast majority the functional significance of PPIs is yet to be elucidated. Molecules targeting specific PPIs of iGlu receptors will thus be important tools for understanding these functions and such molecules are potential leads for developing drugs related to diseases caused by dysfunctional iGlu receptors.

Project
In this project, we are focusing on the interaction of iGlu receptors and a particular important class of scaffolding proteins, the PDZ domain proteins. They regulate activity of iGlu receptors by influencing surface delivery, endocytosis, subcellular location, subunit composition and even intrinsic functional properties. It has been demonstrated that perturbing the PPI between the NMDA receptor and a PDZ domain protein, PSD-95, could protect against ischemic brain damage, without affecting the normal function of the receptor and that this could be a potential treatment for stroke. We have recently identified the most potent inhibitor of this interaction (Angew. Chem. Int. Ed. 2009, 48, 9685-9689).

The objective of this project is to develop potent, selective and cell-permeable inhibitors of this interaction by two complementary methodologies; optimization of our current design by synthesis of novel dimeric ligands and screening of a diverse compound library.