Please use this identifier to cite or link to this item:
Title: Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases
Authors: Xia, Yiyin
To, Janet
Chan, Ning-Yu
Hu, Side
Liew, Heng Tai
Balamkundu, Seetharamsing
Zhang, Xiaohong
Lescar, Julien
Bhattacharjya, Surajit
Tam, James P.
Liu, Chuan-Fa
Keywords: Science::Biological sciences
Issue Date: 2021
Source: Xia, Y., To, J., Chan, N., Hu, S., Liew, H. T., Balamkundu, S., Zhang, X., Lescar, J., Bhattacharjya, S., Tam, J. P. & Liu, C. (2021). Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases. Angewandte Chemie International Edition, 60(41), 22207-22211.
Project: MOE2016-T3-1-003
Journal: Angewandte Chemie International Edition 
Abstract: Peptidyl asparaginyl ligases (PALs) are powerful tools for peptide macrocyclization. Herein, we report that a derivative of Asn, namely Nγ -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 (Ki =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.
ISSN: 1433-7851
DOI: 10.1002/anie.202108125
Rights: © 2021 Wiley-VCH GmbH. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

Citations 50

Updated on Mar 28, 2023

Web of ScienceTM
Citations 50

Updated on Mar 22, 2023

Page view(s)

Updated on Mar 29, 2023

Google ScholarTM




Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.