Various peptide analogues, such as peptoids, have shown promise as protein-binding bioactive compounds, but are hampered by the fact that they are �floppy� molecules with few structural constraints.  Here we report an efficient route to N-substituted alanines, a member of a large class of molecules called peptide tertiary amides or PTAs (N-alkyl peptides).  The presence of a methyl group at the a carbon imparts significant structural constraints to the molecule.  We report the synthesis of a one bead one compound library of enantiopure PTA trimers containing over 100,000 compounds with all possible combinations of R and S enantiomers at each a carbon.  It is demonstrated that low micromolar ligands to a model target protein can be mined from this library and that the methyl groups at Ca are critical for this relatively high affinity.  Large libraries of PTAs are anticipated to be a superior source of leads for the development of useful pharmacological reagents.

Synthesis and screening of stereochemically diverse combinatorial libraries of peptide tertiary amides

244th National Meeting (2012)

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