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 anti‐parallel (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. © 1995 Wiley‐Liss, Inc.