Transition-metal catalyzed post-translational modification of peptides and proteins

The synthesis of labelled or post-translationally modified peptides and proteins represents an important challenge in Chemical Biology, which enables the characterization of these proteins with biophysical and cell-biological methods. While considerable progress in the development of biorthogonal ligation methods has been made over the last two decades, there is still a strong need for new methods that take advantage of natural amino acids to introduce natural and non-natural moieties as seen in posttranslational modifications. In this research project a Pd-catalyzed Tsuji-Trost-allylation will be developed for the prenylation of Cys-containing peptides and proteins, which allows the synthesis of prenylated peptides with high n/iso ratio and excellent chemoselectivity. It is planned to apply this method for the synthesis of farnesylated and geranylgeranylated proteins as well as for the introduction of linker groups that allow subsequent derivatization.

Some endogenous proteins not only consist of amino acids, but are also decorated with fat-like lipid chains, which significantly influence the biological functions of the protein. For example, the Ras protein is only active and carcinogenic if it can bind to the membrane through a "lipid anchor". A better understanding of these body processes would accelerate the development of new drugs and cancer therapies. The effort for such investigations is very high, because complex molecules are required for enzymatic conversions, the production of which takes a lot of time and is associated with high costs. As part of an FWF project, the groups of Rolf Breinbauer from the Institute of Organic Chemistry at TU Graz and Christian F. W. Becker from the Institute of Biological Chemistry at the University of Vienna have developed a much simpler and more direct method of introducing lipids into proteins. With the use of the noble metal palladium and the ligand biphephos they have developed a catalyst system to attach such lipids to proteins with high selectivity and to make them available for biomedical research.