title: 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.
abstract: 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. Beta3-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-beta3 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.
authors.affiliation: Departement für Chemie und Angewandte Biowissenschaften, Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH Hönggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich.
authors.forename: David F
authors.initials: DF
authors.lastname: Hook
authors.forename: Pascal
authors.initials: P
authors.lastname: Bindschädler
authors.forename: Yogesh R
authors.initials: YR
authors.lastname: Mahajan
authors.forename: Radovan
authors.initials: R
authors.lastname: Sebesta
authors.forename: Peter
authors.initials: P
authors.lastname: Kast
authors.forename: Dieter
authors.initials: D
authors.lastname: Seebach
mesh_terms: D008285:Major Histocompatibility Complex; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D010455:Peptides