DPP-4 Cleaves α/β-Peptide Bonds: Substrate Specificity and Half-Lives |
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Authors: | Amila Turalić Prof Jasmina Đeđibegović Dr Zsófia Hegedüs Prof Tamás A Martinek |
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Affiliation: | 1. Department of Pharmaceutical Analysis, University of Sarajevo, Faculty of Pharmacy, Zmaja od Bosne 8, 71 000 Sarajevo, Bosnia and Herzegovina;2. Department of Medical Chemistry, University of Szeged, Faculty of Medicine, 8 Dóm tér, 6720 Szeged, Hungary |
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Abstract: | 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 β3-amino acid side chain and peptide length. Significantly improved half-lives were observed for β3Ile-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. |
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Keywords: | DPP-4 enzyme inhibitors proteolysis peptide bond cleavage α/β-peptides |
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