Naturally occurring peptides and proteins often use dynamic disulfide bonds to impart defined tertiary/quaternary structures for the formation of binding pockets with uniform size and function. Although peptide synthesis and modification are well established, controlling quaternary structure formation remains a significant challenge. Here, we report the facile incorporation of aryl aldehyde and acyl hydrazide functionalities into peptide oligomers via solid-phase copper-catalysed azide–alkyne cycloaddition (SP-CuAAC) click reactions. When mixed, these complementary functional groups rapidly react in aqueous media at neutral pH to form peptide–peptide intermolecular macrocycles with highly tunable ring sizes. Moreover, sequence-specific figure-of-eight, dumbbell-shaped, zipper-like and multi-loop quaternary structures were formed selectively. Controlling the proportions of reacting peptides with mismatched numbers of complementary reactive groups results in the formation of higher-molecular-weight sequence-defined ladder polymers. This also amplified antimicrobial effectiveness in select cases. This strategy represents a general approach to the creation of complex abiotic peptide quaternary structures.

中文翻译：

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动态共价化学能够以完全非生物的方式形成抗菌肽四级组装体

天然存在的肽和蛋白质通常使用动态二硫键赋予确定的三级/四级结构，以形成大小和功能均一的结合口袋。尽管肽合成和修饰已被很好地建立，但是控制季结构的形成仍然是一个重大挑战。在这里，我们报告了通过固相铜催化的叠氮化物-炔烃环加成反应（SP-CuAAC）的点击反应，将芳基醛和酰肼官能团容易地掺入肽低聚物中。当混合时，这些互补的官能团在水性介质中于中性pH下快速反应，形成具有高度可调环大小的肽-肽分子间大环。此外，有选择地形成了序列特定的八字形，哑铃形，拉链状和多环四元结构。控制具有不匹配数目的互补反应基团的反应肽的比例导致形成更高分子量的序列定义的梯形聚合物。在某些情况下，这也增强了抗菌效力。该策略代表了创建复杂的非生物肽四级结构的通用方法。