COMPARISON OF THE PROTEOLYTIC SUSCEPTIBILITIES OF HOMOLOGOUS L-AMINO-ACID, D-AMINO-ACID, AND N-SUBSTITUTED GLYCINE PEPTIDE AND PEPTOID OLIGOMERS

A series of homologous L-amino acid, D-amino acid, and both parallel and antiparallel (retro) sequence N-substituted glycine peptide and peptoid oligomers were prepared and incubated with a series of enzymes representative of the major classes of proteases. Each respective L-amino acid containing peptide sequence was readily cleaved by the appropriate enzyme, namely Ac-L-ala-L-leu-L-phe-L-ala-L-leu-L-arg-NH2 by chymotrypsin, Ac-L-ala-L-ala-L-ala-L-leu-L-phe-L-arg-NH2 by elastase, Ac-L-ala-L-phe-L-glu-L-leu-L-ala-L-ala-NH2 by papain, Z-L-ala-L-his-L-phe-L-phe-L-arg-L-leu-NH2 by pepsin, Ac-L-phe-L-ala-L-arg-L-ala-L-arg-L-asp-NH2 by trypsin, and Ac-L-ala-L-tyr-Lala-L-phe-OH for carboxypeptidase A. In contrast, equivalent D-amino acid containing and N-substituted glycine containing oligomers were cleaved minimally or not at all by the respective enzymes. The N-substituted glycine peptoids represent a new class of combinatorial diversity for lead discovery with improved pharmaceutical characteristics relative to L-amino acid containing peptides. (C) 1995 Wiley-Liss, Inc.