The proteolytic stability of 'designed' β-peptides containing α-peptide-bond mimics and of mixed α,β-peptides:: Application to the construction of MHC-binding peptides

Whereas a-peptides are rapidly degraded in vivo and in vitro by a multitude of peptidases, substrates constructed entirely of or incorporating homologated alpha-amino acid (i.e., beta-amino acid) units exhibit a superior stability profile. Efforts made so far to protcolytically hydrolyze a beta-beta 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 alpha-peptidic amide bonds. Increasing the prospect for degradation would permit the tuning of beta-peptide stability; here, however, no cleavage was observed (1, 2, 4 - 6, Table 1). Peptides comprised of alpha- and beta-amino acids (mixed alpha,beta-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. beta(3)-Peptides containing alpha-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 alpha-beta peptide bond, namely that of alpha Ala-beta(3)hAla. Significantly, successful hydrolysis is independent of the configuration of the beta-amino acid. Some of the alpha,beta-peptides discussed here are being investigated for their binding affinities to class I MHC proteins. The computer-programming steps required to prepare alpha,beta-peptides on an automated peptide synthesizer are presented.