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Proteolytically stable peptides by incorporation of α‐Tfm amino acids
Author(s) -
Koksch Beate,
Sewald Norbert,
Hofmann HansJörg,
Burger Klaus,
Jakubke HansDieter
Publication year - 1997
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(199705)3:3<157::aid-psc94>3.0.co;2-w
Subject(s) - steric effects , chemistry , stereochemistry , peptide , amino acid , proteolysis , serine , chymotrypsin , side chain , proteolytic enzymes , serine protease , trypsin , protease , active site , trifluoromethyl , cleavage (geology) , enzyme , biochemistry , organic chemistry , geotechnical engineering , fracture (geology) , engineering , polymer , alkyl
A series of model peptides containing α‐trifluoromethyl‐substituted amino acids in five different positions relative to the predominant cleavage site of the serine protease α‐chymotrypsin was synthesized by solution methods to investigate the influence of α‐Tfm substitution on the proteolytic stability of peptides. Proteolysis studies demonstrated absolute stability of peptides substituted in the P 1 position and still considerable proteolytic stability for peptides substituted at the P 2 and P′ 2 positions compared with the corresponding unsubstituted model peptide. Comparison with peptides containing the fluorine‐free disubstituted amino acid α‐aminoisobutyric acid allowed to separate electronic from steric effects. Furthermore, the absolute configuration of the α‐Tfm‐substituted amino acid was found to exert considerable effects on the proteolytic stability, especially in P′ 1 substituted peptides. Investigations of this phenomenon using empirical force field calculations revealed that in the ( S,R,S )‐diasteromer the steric constraints exhibited by the α‐Tfm group can be outweighed by an advantageous interaction of the fluorine atoms with the serine side chain of the enzyme. In contrast, a favourable interaction between substrate and enzyme is impossible for the ( S,S,S )‐diastereomer. © 1997 European Peptide Society and John Wiley & Sons, Ltd.