Insight to the residue in P2 position prevents the peptide inhibitor from being hydrolyzed by serine proteases. Issue 6 (2nd June 2020)

• Record Type: Journal Article
• Authors: Xue, Guangpu; Xie, Xie; Zhou, Yang; Yuan, Cai; Huang, Mingdong; Jiang, Longguang
• Is Part Of: Bioscience, biotechnology, and biochemistry. Volume 84:Issue 6(2020)
• Page Start: 1153
• Page End: 1159
• Publication Date: 2020-06-02
• Subjects: Cyclic peptide inhibitor -- upain-1-W3F -- crystal structure -- uPA -- serine protease; Biotechnology -- Periodicals; Biochemistry -- Periodicals; 660.6
• DOI: 10.1080/09168451.2020.1723405
• Languages: English
• ISSNs: 0916-8451

Abstract

ABSTRACT: Peptidic inhibitors of proteases are attracting increasing interest not only as drug candidates but also for studying the function and regulation mechanisms of these enzymes. Previously, we screened out a cyclic peptide inhibitor of human uPA and found that Ala substitution of P2 residue turns upain-1 to a substrate. To further investigate the effect of P2 residue on the peptide behavior transformation, we constructed upain-1-W3F, which has Phe replacement in the P2 position. We determined K D and Ki of upain-1-W3F and found that upain-1-W3F might still exist as an inhibitor. Furthermore, the high-resolution crystal structure of upain-1-W3F·uPA reveals that upain-1-W3F indeed stays as an intact inhibitor bind to uPA. We thus propose that the P2 residue plays a nonnegligible role in the conversion of upain-1 to a substrate. These results also proposed a strategy to optimize the pharmacological properties of peptide-based drug candidates by hydrophobicity and steric hindrance. Abbreviations : uPA: urokinase-type plasminogen activator; SPD: serine protease domain; S1 pocket: specific substrate-binding pocket Graphical abstract: : Crystal structure of upain-1-W3F·uPA suggests P2 residue of upain-1 series as a key factor in the conversion of upain-1 to a slow substrate.