Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Jezik: | English |
| Izdano: |
2022
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| Online dostop: | https://hdl.handle.net/10356/163147 |
| _version_ | 1826110621935992832 |
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| author | 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 |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 |
| author_sort | Xia, Yiyin |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T02:37:13Z |
| format | Journal Article |
| id | ntu-10356/163147 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:37:13Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1631472022-11-25T02:46:30Z Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases 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 School of Biological Sciences Singapore-MIT Alliance for Research and Technology Science::Biological sciences Amino Acids Enzymes 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. Ministry of Education (MOE) Nanyang Technological University This research was supported by Academic Research Fund(AcRF) Tier 3 (MOE2016-T3-1-003) grants to J.P.T., J.L., andC.-F.L. laboratories and by AcRF Tier 1 (2019-T1-002-100) and NTUitive Gap grant NGF-2019-07-029 to C.-F.L. from the Singapore Ministry of Education (MOE). 2022-11-25T02:46:30Z 2022-11-25T02:46:30Z 2021 Journal Article 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 1433-7851 https://hdl.handle.net/10356/163147 10.1002/anie.202108125 34396662 2-s2.0-85114370221 41 60 22207 22211 en MOE2016-T3-1-003 2019-T1-002-100 NGF-2019-07-029 Angewandte Chemie International Edition © 2021 Wiley-VCH GmbH. All rights reserved. |
| spellingShingle | Science::Biological sciences Amino Acids Enzymes 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 Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases |
| title | Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases |
| title_full | Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases |
| title_fullStr | Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases |
| title_full_unstemmed | Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases |
| title_short | Nγ-hydroxyasparagine: a multifunctional unnatural amino acid that is a good P1 substrate of asparaginyl peptide ligases |
| title_sort | nγ hydroxyasparagine a multifunctional unnatural amino acid that is a good p1 substrate of asparaginyl peptide ligases |
| topic | Science::Biological sciences Amino Acids Enzymes |
| url | https://hdl.handle.net/10356/163147 |
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