Research in the Chemical Biology Group
Chemical biology is a highly interdisciplinary science, which applies chemical approaches to the study of molecular events in biological systems. The main focus of the Chemical Biology group at University of Copenhagen (FARMA) is the study of integral membrane proteins, such as ion channels, receptors and transporters, in the central nervous system (CNS), which examines the structure and function of these proteins at the molecular level. The research follows two approaches: 1) Perturbation of protein function using small molecule ligands, and 2) Probing biological activity by the incorporation of unnatural amino acids into proteins.
Small-molecule ligands
We use naturally occurring toxins, particularly those from wasps, spiders and cone snails, as a starting point in the development of ligands for membrane-bound proteins in the CNS, and potentially as leads in the treatment of diseases of the brain. Generally, we use solid-phase synthesis methodologies for the rapid and efficient generation of libraries of analogs that are subsequently tested in biological assays. Recently, we have also begun studying small molecules as inhibitors of protein-protein interactions. Specifically, we are targeting the interaction between integral membrane proteins and intracellular scaffolding proteins.
Unnatural amino acids in proteins
The genetic vocabulary encodes 20 amino acids with a finite number of functionalities. Nature has overcome this limitation by using posttranslational modification to introduce functionalities not attainable by genetic methods. We are attempting to harness these capabilities in applying protein engineering beyond the genetic code via two core technologies: Suppression mutagenesis and expressed protein ligation (EPL). In the former technology, a tRNA is chemically charged with an unnatural amino acid, which is site-specifically incorporated into the protein using the machinery of the cell. For example, we use this technology in studies of the serotonin transporter (SERT), an important protein responsible for re-uptake of serotonin and a target for antidepressants. EPL combines advantages of molecular biology with chemical peptide synthesis, and enables the addition of unnatural functionality to a recombinant protein framework. In our group EPL is applied to the study of glutamate receptor ion channels.
