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The Outstanding Biological Stability of β ‐ and γ ‐Peptides toward Proteolytic Enzymes: An In Vitro Investigation with Fifteen Peptidases
Author(s) -
Frackenpohl Jens,
Arvidsson Per I.,
Schreiber Jürg V.,
Seebach Dieter
Publication year - 2001
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/1439-7633(20010601)2:6<445::aid-cbic445>3.0.co;2-r
Subject(s) - proteolytic enzymes , in vitro , biochemistry , chemistry , enzyme , peptide hydrolases , computational biology , biology , protease
A series of 36 linear and cyclic β ‐ and γ ‐peptides consisting of as few as two, and as many as 15 residues, was offered as substrates to 15 commercially available proteases of bacterial, fungal, and eukaryotic origin, including a β ‐lactamase and amidases, as well as most vigorous, nonspecific proteases, such as the 20 S proteasome from human erythrocytes. For comparison, an α ‐eicosapeptide and standard substrates of the proteolytic enzymes were included in the investigation. Under conditions of complete cleavage of the α ‐peptide within 15 min the β ‐ and γ ‐peptides were stable for at least 48 h. Inhibition studies with seven β ‐ and γ ‐peptides and α‐chymotrypsin show that the residual enzyme activity toward succinyl‐Ala‐Ala‐Pro‐Phe‐ p ‐nitroanilide is unchanged within experimental error after incubation for 15 min with the peptide analogues. Thus , β ‐ and γ ‐peptides with proteinogenic side chains, that is, consisting of the singly or doubly homologated natural α ‐amino acids (one or two CH 2 groups inserted in the backbone of each residue), are completely stable to common proteases, without inhibiting their normal activity (as demonstrated for α‐chymotrypsin). This proteolytic stability of peptides built of homologated amino acids is a prerequisite for their potential use as drugs.