Bioconjugate Platform for Iterative Backbone N-Methylation of Peptides.
Bioconjugate Platform for Iterative Backbone N-Methylation of Peptides.
复制标题
DOI：
10.1021/acscatal.2c04681
复制
发表时间：
2022-10
期刊：
影响因子：
12.9
通讯作者：
Yiwu Zheng;C. Ongpipattanakul;S. Nair
中科院分区：
文献类型：
--
作者：
Yiwu Zheng;C. Ongpipattanakul;S. Nair
肽骨架的N-甲基化经常被用作开发肽药物的策略。然而，化学合成中的困难、对映体纯N-甲基结构单元的高成本以及随后的偶联效率低下阻碍了大规模的药用化学努力。在这里，我们提出了一种化学酶的策略，通过生物共轭的肽的利益，一个borosin型甲基转移酶的催化支架的骨架N-甲基化。来自玫瑰小菇的底物耐受酶的晶体结构指导了可以通过异双功能交联剂连接到任何选择的肽底物的解耦催化支架的设计。与支架连接的肽，包括具有非蛋白质残基的肽，显示出稳健的骨架N-甲基化。测试了各种交联策略以促进底物分解，这使得可逆的生物缀合方法能够有效释放修饰的肽。我们的研究结果提供了一个框架的骨干N-甲基化的任何肽的利益，并可能促进生产大库的N-甲基化的肽。
N-methylation of peptide backbones has often been utilized as a strategy towards the development of peptidic drugs. However, difficulties in the chemical synthesis, high cost of enantiopure N-methyl building blocks, and subsequent coupling inefficiencies have hampered larger-scale medicinal chemical efforts. Here, we present a chemoenzymatic strategy for backbone N-methylation by bioconjugation of peptides of interest to the catalytic scaffold of a borosin-type methyltransferase. Crystal structures of a substrate tolerant enzyme from Mycena rosella guided the design of a decoupled catalytic scaffold that can be linked via a heterobifunctional crosslinker to any peptide substrate of choice. Peptides linked to the scaffold, including those with non-proteinogenic residues, show robust backbone N-methylation. Various crosslinking strategies were tested to facilitate substrate disassembly, which enabled a reversible bioconjugation approach that efficiently released modified peptide. Our results provide general framework for the backbone N-methylation on any peptide of interest and may facilitate the production of large libraries of N-methylated peptides.