Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/163147
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. https://dx.doi.org/10.1002/anie.202108125
Project: MOE2016-T3-1-003
2019-T1-002-100
NGF-2019-07-029
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.
URI: https://hdl.handle.net/10356/163147
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

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