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

• Published in: Chemistry & biodiversity 2005-05, Vol.2 (5), p.591-632
• Main Authors: Hook, David F., Bindschädler, Pascal, Mahajan, Yogesh R., Šebesta, Radovan, Kast, Peter, Seebach, Dieter
• Format: Article
• Language: English
• Subjects: Major Histocompatibility Complex; Molecular Mimicry; Peptides - chemistry; Peptides - metabolism; Protein Binding; Protein Conformation
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.200590039

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.