The Proteolytic Stability of ‘Designed’β-Peptides Containingα-Peptide-Bond Mimics and of Mixedα,β-Peptides: Application to the Construction of MHC-Binding Peptides

Whereas α-peptides are rapidly degraded in vivo and in vitro by a multitude of peptidases, substrates constructed entirely of or incorporating homologated α-amino acid (i.e., β-amino acid) units exhibit a superior stability profile. Efforts made so far to proteolytically hydrolyze a ββ peptide bond have not proved fruitful; a study aimed at breaching this proteolytic stability is discussed here. A series of such bonds have been designed with side-chain groups similar in relative positions (constitution) and three-dimensional arrangements (configuration) as found about α-peptidic amide bonds. Increasing the prospect for degradation would permit the tuning of β-peptide stability; here, however, no cleavage was observed (1, 2, 4–6, Table 1). Peptides comprised of α- and β-amino acids (mixed α,β-peptides, 8–11) are expected to benefit from both recognition by a natural receptor and a high level of proteolytic stability, ideal characteristics of pharmacologically active compounds. β3-Peptides containing α-amino acid moieties at the N-terminus are degraded, albeit slowly, by several peptidases. Of particular interest is the ability of pronase to cleave an αβ peptide bond, namely that of αAlaβ3hAla. Significantly, successful hydrolysis is independent of the configuration of the β-amino acid. Some of the α,β-peptides discussed here are being investigated for their binding affinities to class I MHC proteins. The computer-programming steps required to prepare α,β-peptides on an automated peptide synthesizer are presented.