Angewandte Chemie - International Edition p. 22207 - 22211 (2021)
Update date:2022-09-26
Topics:
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
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.
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Doi:10.1002/1521-3773(20000818)39:16<2877::AID-ANIE2877>3.0.CO;2-V
(2000)Doi:10.1021/acs.orglett.1c01734
(2021)Doi:10.1016/j.tetlet.2006.12.044
(2007)Doi:10.1055/s-2006-933117
(2006)Doi:10.1016/0008-6215(93)84069-I
(1993)Doi:10.1021/jo034148n
(2003)