Directed Evolution of Stable, Orally Bioavailable S-U-P-R Peptides

Peptides have poor biostability and natural sequences cannot readily be converted into drug-like molecules.  We have adapted mRNA display to evolve highly stabilized versions of peptides while retaining function toward their intended target.  To do this, we incorporated an unnatural 21st amino acid in a combinatorial scanning library and subjected this pool to proteolysis prior to selection for function.  These experiments have resulted several new dramatically stabilized "SUPR peptides" (scanning unnatural protease resistant) that show half lives in human serum of several days to one week.  One utility of these SUPR peptides is that it may be adapted to give an in vivo half-life of >18 hours in the mouse and an oral bioavailability of >10%.  Experiments to analyze the structure and function of these peptides will be discussed.