Peptide modification by incorporation of alpha-trifluoromethyl substituted amino acids

Metabolic stabilization of pharmacologically active peptides can be achieved by incorporation of sterically hindered non-natural amino acids, e.g. C-alpha,C-alpha-disubstituted amino acids. alpha-Trifluoromethyl substituted amino acids, a subclass of C-alpha,C-alpha-disubstituted amino acids, also fulfil this requirement while featuring additional properties based on the electronic influence of the fluorine substituents. This review summarizes the results concerning the stability of peptides containing alpha-TFM amino acids towards proteolysis by alpha-chymotrypsin, Furthermore, configurational effects of alpha-TFMAla on the proteolytic stability of peptides are explained using empirical force field calculations. The influence of alpha-TFMAla incorporation on the secondary structure of selected tripeptide amides is compared to the effects exerted by its fluorine-free analogue, aminoisobutyric acid. Finally, results on metabolic stabilization and biological activity of modified thyrotropin releasing hormone are interpreted.