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N γ ‐Hydroxyasparagine: A Multifunctional Unnatural Amino Acid That is a Good P1 Substrate of Asparaginyl Peptide Ligases
Author(s) -
Xia Yiyin,
To Janet,
Chan NingYu,
Hu Side,
Liew Heng Tai,
Balamkundu Seetharamsing,
Zhang Xiaohong,
Lescar Julien,
Bhattacharjya Surajit,
Tam James P.,
Liu ChuanFa
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202108125
Subject(s) - cyclic peptide , peptide , chemistry , hydroxamic acid , moiety , stereochemistry , pharmacophore , native chemical ligation , peptidomimetic , combinatorial chemistry , substrate (aquarium) , amino acid , biochemistry , cysteine , enzyme , biology , ecology
Abstract Peptidyl asparaginyl ligases (PALs) are powerful tools for peptide macrocyclization. Herein, we report that a derivative of Asn, namely N γ ‐hydroxyasparagine or Asn(OH), is an unnatural P1 substrate of PALs. By Asn(OH)‐mediated cyclization, we prepared cyclic peptides as new matrix metalloproteinase 2 (MMP2) inhibitors displaying the hydroxamic acid moiety of Asn(OH) as the key pharmacophore. The most potent cyclic peptide ( K i =2.8±0.5 nM) was built on the hyperstable tetracyclic scaffold of rhesus theta defensin‐1. The Asn(OH) residue in the cyclized peptides can also be readily oxidized to Asp. By this approach, we synthesized several bioactive Asp‐containing cyclic peptides (MCoTI‐II, kB2, SFTI, and integrin‐targeting RGD peptides) that are otherwise difficult targets for PAL‐catalyzed cyclization owing to unfavorable kinetics of the P1‐Asp substrates. This study demonstrates that substrate engineering is a useful strategy to expand the application of PAL ligation in the synthesis of therapeutic cyclic peptides.