The Proteolytic Stability of 'Designed' beta-Peptides Containing alpha-Peptide-Bond Mimics and of Mixed alpha,beta-Peptides:Application to the Construction of MHC-Binding Peptides

摘要

Whereas alpha-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 proteolytically 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 alphaAla-beta~3hAla.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.