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|Title:||Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases||Authors:||Xia, Yiyin
Liew, Heng Tai
Tam, James P.
|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
|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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