DPP-4 Cleaves alpha/beta-Peptide Bonds: Substrate Specificity and Half-Lives

Turalic, Amila; Dedibegovic, Jasmina; Hegedus, Zsofia ✉ [Hegedüs, Zsófia (gyógyszerkémia), szerző] Orvosi Vegytani Intézet (SZTE / ÁOK); Martinek, Tamas A. ✉ [Martinek, Tamás (Gyógyszerkémia), szerző] Orvosi Vegytani Intézet (SZTE / ÁOK)

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: CHEMBIOCHEM 1439-4227 1439-7633 21 (14) pp. 2060-2066 2020
  • SJR Scopus - Organic Chemistry: Q1
The incorporation of beta-amino acids into a peptide sequence has gained particular attention as beta- and alpha/beta-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 alpha-peptide bonds. In this study, a series of analogs of dipeptidyl peptidase-4 (DPP-4) substrate inhibitors were synthesized in order to investigate whether beta-amino acid homologation at the scissile bond could be a valid approach to improving peptide stability towards DPP-4 degradation. DPP-4 cleaved the alpha/beta-peptide bond after the N-terminal penultimate Pro with a broad specificity and retained full activity regardless of the beta(3)-amino acid side chain and peptide length. Significantly improved half-lives were observed for beta(3)Ile-containing peptides. Replacing the penultimate Pro with a conformationally constrained Pro mimetic led to proteolytic resistance. DPP-4 cleavage of alpha/beta-peptide bonds with a broad promiscuity represents a new insight into the stability of peptide analogs containing beta-amino acids as such analogs were thought to be stable towards enzymatic degradation.
Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
2020-11-27 11:44