Metabolic stabilization of pharmacologically active peptides can be ac
hieved by incorporation of sterically hindered non-natural amino acids
, e.g. C-alpha,C-alpha-disubstituted amino acids. alpha-Trifluoromethy
l 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 substitue
nts. This review summarizes the results concerning the stability of pe
ptides containing alpha-TFM amino acids towards proteolysis by alpha-c
hymotrypsin, Furthermore, configurational effects of alpha-TFMAla on t
he proteolytic stability of peptides are explained using empirical for
ce field calculations. The influence of alpha-TFMAla incorporation on
the secondary structure of selected tripeptide amides is compared to t
he effects exerted by its fluorine-free analogue, aminoisobutyric acid
. Finally, results on metabolic stabilization and biological activity
of modified thyrotropin releasing hormone are interpreted.