Light-initiated 1,3-dipolar cycloaddition between dehydroalanines and tetrazoles: application to late-stage peptide and protein modifications.
Light-initiated 1,3-dipolar cycloaddition between dehydroalanines and tetrazoles: application to late-stage peptide and protein modifications.
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DOI：
10.1039/d3sc02818f
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发表时间：
2023-09-13
期刊：
影响因子：
8.4
通讯作者：
Li, Yanmei
中科院分区：
文献类型：
--
作者：
Zhang, Mengqian;He, Peiyang;Li, Yanmei
作为一种易于引入的非编码氨基酸，具有不同于 20 种天然氨基酸的独特亲电性，脱氢丙氨酸 (Dha) 不仅是一种精确的蛋白质翻译后修饰 (PTM) 插入工具，也是一种有前途的肽和蛋白质的多功能标记位点。然而，在反应速率和温和反应条件之间实现平衡一直是开发新型 Dha 修饰策略的主要挑战。快速、高效且温和的 Dha 修饰策略是非常需要的。此外，用于含 Dha 肽和蛋白质修饰的无催化剂光控反应尚未开发。在这里，我们报道了 Dha 和 2,5-二芳基四唑之间的光引发 1,3-偶极环加成反应。在低功率紫外灯照射下，该反应在几分钟内完成，无需催化，产生对 Dha 残基具有优异化学选择性的荧光吡唑啉修饰肽或蛋白质。值得注意的是，该反应在硫链丝菌肽（一种含有多个 Dha 残基（Dha3、Dha16 和 Dha17）的天然抗菌肽）的修饰中表现出完全的位点特异性，可在 20 分钟内实现高产率。这是目前修饰硫链丝菌素中 Dha 残基最快的反应，对 Dha16 具有明确的位点特异性。这种光引发反应还为蛋白质的精确功能化提供了化学选择性策略。此外，反应的快速性和效率最大限度地减少了紫外线对生物反应系统的损害。结合荧光特性，这种光控方法可应用于活细胞成像，进一步拓宽了 Dha 修饰方法的应用范围。报道了一种有效的脱氢丙氨酸环加成修饰策略，该策略能够在温和的非催化反应条件下快速生成荧光吡唑啉修饰的肽和蛋白质。
As an easily introduced noncoded amino acid with unique electrophilicity distinct from the 20 natural amino acids, dehydroalanine (Dha) is not only a precise protein post-translational modification (PTM) insertion tool, but also a promising multifunctional labelling site for peptides and proteins. However, achieving a balance between the reaction rate and mild reaction conditions has been a major challenge in developing novel Dha-modified strategies. Rapid, efficient, and mild Dha modification strategies are highly desired. Additionally, catalyst-free photocontrollable reactions for Dha-containing peptide and protein modification have yet to be developed. Here, we report a photoinitiated 1,3-dipolar cycloaddition reaction between Dha and 2,5-diaryl tetrazoles. Under low-power UV lamp irradiation, this reaction is completed within minutes without catalysis, resulting in a fluorescent pyrazoline-modified peptide or protein with excellent chemoselectivity for Dha residues. Notably, this reaction exhibits complete site-specificity in the modification of thiostrepton, a natural antimicrobial peptide containing multiple Dha residues (Dha3, Dha16, and Dha17), within 20 minutes in high yields. This is currently the fastest reaction for modifying the Dha residue in thiostrepton with clear site-specificity towards Dha16. This photoinitiated reaction also provides a chemoselective strategy for precise functionalization of proteins. Additionally, the rapidity and efficiency of the reaction minimize UV light damage to the biological reaction system. Combined with fluorogenic properties, this photo-controllable methodology can be applied to live cell imaging, further broadening the application scope of the Dha modification methodology. An efficient strategy for dehydroalanine cycloaddition modification was reported, which enables rapid generation of fluorescent pyrazoline-modified peptides and proteins under mild, non-catalytic reaction conditions.
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