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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
Author(s) -
Hook David F.,
Bindschädler Pascal,
Mahajan Yogesh R.,
Šebesta Radovan,
Kast Peter,
Seebach Dieter
Publication year - 2005
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200590039
Subject(s) - chemistry , peptide , peptide bond , amino acid , cleave , proteolytic enzymes , pronase , stereochemistry , peptide sequence , biochemistry , combinatorial chemistry , trypsin , enzyme , gene
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. β 3 ‐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 α Ala β 3 hAla. 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.