Nγ-Hydroxyasparagine: A Multifunctional Unnatural Amino Acid That is a Good P1 Substrate of Asparaginyl Peptide Ligases,Angewandte Chemie International Edition

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Nγ-Hydroxyasparagine: A Multifunctional Unnatural Amino Acid That is a Good P1 Substrate of Asparaginyl Peptide Ligases
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2021-08-15 , DOI: 10.1002/anie.202108125
Yiyin Xia ₁ , Janet To ₁ , Ning-Yu Chan ₁ , Side Hu ₁ , Heng Tai Liew ₁ , Seetharamsing Balamkundu _{1,

2} , Xiaohong Zhang ₁ , Julien Lescar ₁ , Surajit Bhattacharjya ₁ , James P Tam ₁ , Chuan-Fa Liu ₁

Affiliation

Peptidyl asparaginyl ligases (PALs) are powerful tools for peptide macrocyclization. Herein, we report that a derivative of Asn, namely N^γ-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 (K_i=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.

中文翻译：

Nγ-羟基天冬酰胺：一种多功能非天然氨基酸，是天冬酰胺肽连接酶的良好 P1 底物

肽基天冬酰胺基连接酶 (PAL) 是肽大环化的有力工具。在此，我们报告了 Asn 的衍生物，即N ^γ -羟基天冬酰胺或 Asn(OH)，是 PAL 的非天然 P1 底物。通过 Asn(OH) 介导的环化，我们制备了环肽作为新的基质金属蛋白酶 2 (MMP2) 抑制剂，显示 Asn(OH) 的异羟肟酸部分作为关键药效团。最有效的环肽（K _i=2.8±0.5 nM) 建立在恒河猴 theta defensin-1 的超稳定四环支架上。环化肽中的 Asn(OH) 残基也很容易被氧化成 Asp。通过这种方法，我们合成了几种含有生物活性 Asp 的环肽（MCoTI-II、kB2、SFTI 和靶向整合素的 RGD 肽），由于 P1-Asp 底物的不利动力学，这些环肽是 PAL 催化环化的困难目标。这项研究表明，底物工程是一种有用的策略，可以扩大 PAL 连接在治疗性环肽合成中的应用。

更新日期：2021-09-27

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