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Publication Abstract from PubMed

Peptidic inhibitors of proteases are attracting increasing interest not only as drug candidates but also for studying the function and regulation mechanisms of these [Formula: see text] out a cyclic peptide inhibitor of human uPA (upain-1, CSWRGLENHRMC) 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 KD 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.

Insight to the residue in P2 position prevents the peptide inhibitor from being hydrolyzed by serine proteases.,Xue G, Xie X, Zhou Y, Yuan C, Huang M, Jiang L Biosci Biotechnol Biochem. 2020 Feb 5:1-7. doi: 10.1080/09168451.2020.1723405. PMID:32019421^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.