Medicinal Chemistry Research
Jagtvej 162, 2100 København Ø
The main aim of my PhD project is to explore the threrapeutic relevance of the protein-protein interaction (PPI) between the GABAB (GABABR)receptor and the K+-channel tetramerization-domain (KCTD) proteins. More specifically, I am using SPOT and microarray technology to genarate peptide inhibitors libraries targeting KCTDs.
PPIs are crucial for most cellular and biochemical process and represent a novel and promising class of drug targets. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS), mediating slow synaptic inhibition via activation of pre- and postsynaptic receptors. It has been shown that GABABRs are involved in cell growth and survival, as well as, in the differentiation, migration and axon guidance of nerve cells. Consequently, GABABR dysfunction has been implicated in severe neurological disorders such as epilepsy, spasticity, depression, anxiety, schizophrenia and cognitive deficits. However, therapeutics targeting GABABRs are limited and baclofen (Lioresal®), used to treat spasticity, remains the only approved drug targeting the GABABR, but serious adverse effects limit its broader use. However, much of the functional diversity observed in GABABR is believed to arise from the interaction with a range of receptor-associated intracellular partner proteins. More specifically, recently functional proteomics studies have revealed that GABABRs in rodent brains are high-molecular weight complexes consisting of two GABABR subunits (GABAB1R, GABAB2R) and a subfamily of the KCTD proteins (KCTD8/12/12b/16). KCTDs are soluble proteins that bind directly to the C-terminus of GABABR subunit 2 (GABAB2R) to stabilize G protein binding, and furthermore, KCTDs interact directly with G protein subunits to modulate canonical GABABR downstream signaling pathways.