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Sortase A‐mediated synthesis of ligand‐grafted cyclized peptides for modulating a model protein‐protein interaction
Author(s) -
Zhang Jing,
Yamaguchi Satoshi,
Nagamune Teruyuki
Publication year - 2015
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201500013
Subject(s) - cyclic peptide , peptide , chemistry , sortase a , tetrapeptide , linker , proteolysis , sortase , ligand (biochemistry) , biochemistry , combinatorial chemistry , receptor , enzyme , bacterial protein , computer science , gene , operating system
Specific ligand‐grafted cyclic peptides are promising drug candidates that can modulate protein‐protein interactions (PPIs) with increased proteolytic stability. In this study, we aimed to demonstrate that Sortase A (SrtA)‐mediated peptide transpeptidation can be applied to produce bioactive sequence‐grafted, stable, cyclic peptides. A naturally occurring cyclic peptide, sunflower trypsin inhibitor 1 (SFTI‐1), was selected as the scaffold, and a tetrapeptide motif, Glu‐Ser‐Asp‐Val (ESDV), was grafted into the scaffold as a model ligand. The linear precursor of the grafted peptide with SrtA‐recognition motifs at the N‐ and C‐termini was cyclized in good yield simply by co‐incubation with SrtA. The ESDV‐grafted cyclic SFTI‐1 obtained was confirmed to have high stability against proteolysis by human serum and bound to the target PDZ2 domain of postsynaptic density‐95 protein. An optimized sequence‐grafted cyclic SFTI‐1 could competitively suppress the interaction of PDZ2 with its natural ligand, the C‐terminal peptide of the NR2B subunit of the N ‐methyl‐D‐aspartate receptor. These results show that a strategy combining peptide grafting into the SFTI‐1 scaffold with SrtA‐catalyzed cyclization can be a simple and effective method for producing stable peptide drugs.