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DPP‐4 Cleaves α/β‐Peptide Bonds: Substrate Specificity and Half‐Lives
Author(s) -
Turalić Amila,
Đeđibegović Jasmina,
Hegedüs Zsófia,
Martinek Tamás A.
Publication year - 2020
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/cbic.202000050
Subject(s) - scissile bond , peptide , cleave , peptide bond , chemistry , amino acid , stereochemistry , peptide sequence , proteolytic enzymes , cleavage (geology) , dipeptidyl peptidase , enzyme , biochemistry , protease , biology , paleontology , fracture (geology) , gene
The incorporation of β‐amino acids into a peptide sequence has gained particular attention as β‐ and α/β‐peptides have shown remarkable proteolytic stability, even after a single homologation at the scissile bond. Several peptidases have been shown to cleave such bonds with high specificity but at a much slower rate compared to α‐peptide bonds. In this study, a series of analogs of dipeptidyl peptidase‐4 (DPP‐4) substrate inhibitors were synthesized in order to investigate whether β‐amino acid homologation at the scissile bond could be a valid approach to improving peptide stability towards DPP‐4 degradation. DPP‐4 cleaved the α/β‐peptide bond after the N‐terminal penultimate Pro with a broad specificity and retained full activity regardless of the β 3 ‐amino acid side chain and peptide length. Significantly improved half‐lives were observed for β 3 Ile‐containing peptides. Replacing the penultimate Pro with a conformationally constrained Pro mimetic led to proteolytic resistance. DPP‐4 cleavage of α/β‐peptide bonds with a broad promiscuity represents a new insight into the stability of peptide analogs containing β‐amino acids as such analogs were thought to be stable towards enzymatic degradation.