G Protein Antagonists: Structural Determinants for Subtype-Selectivity

In many instances, the identification of a new gene creates the perception in the general public that the cure for a given disease is around the corner. In fact, there is a long way to go from the discovery of a gene (or of its role in a disease) to the design e.g. of an inhibitor of the gene product and many issues need to be addressed. In the present project, we searched for inhibitors of G proteins. G proteins are molecular switches that relay the signal generated by a receptor (e.g. a hormone or neurotransmitter that bind son the cell surface) to the interior of the cell. Based on the sequence of the human genome, the number of G protein-coupled receptors can be estimated to exceed 1000; in contrast, the number of G protein oligomers is substantially lower. There are arguments in favour or against the concept of direct inhibition of G proteins. In the current project, we explored this concept and its predictions and we provided a proof of principle: G protein inhibitors can be selective and that new types of selectivity can result from their site of action at the interface between receptors and G proteins. Many distinct receptors interact with the same G protein; however, the surface of the G protein that is covered by individual receptors is distinct; this subtle differences provide for new- hitherto unappreciated - forms of selectivity. Obviously, drug development is not the job of academic pharmacology (this is done by the pharmaceutical industry); pharmacology as a basic science focuses on mechanisms of action and on investigating new principles of drug action. A concept can be easily formulated based on theoretical considerations, the experimental proof is the litmus test which is fulfilled if predictions can be verified. In the current project, these goals were pursued and achieved with a reasonable success. The latter is documented by the publications which have attracted some interest in the field (cf. Science Citation Index). It is nevertheless evident that our insights do have some re-per- cussions on and implications for drug development.