Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling.
Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling.
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DOI：
10.1002/anie.201502607
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发表时间：
2015-07-20
期刊：
影响因子：
--
通讯作者：
Dawson PE
中科院分区：
文献类型：
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作者：
Assem N;Ferreira DJ;Wolan DW;Dawson PE
大环化是一种广泛应用的方法，用于克服线性肽本质上无序的性质。例如，人们已经做出了重大努力，通过束缚近端侧链来稳定 α 螺旋结构。虽然这些方法成功地模拟了蛋白质 α-螺旋，但系链的结构要求通常会阻止对螺旋非结合面的进一步合成修饰。在这里，我们展示了二氯丙酮（DCA）在引入肽亲核试剂（例如硫醇）之间以产生丙酮（ACE）连接的桥时增强螺旋二级结构的效用。除了稳定螺旋结构外，嵌入接头中的酮部分还可以使用具有不同分子标签的肟连接进行修饰。通过与 RNAse S 复合的受限 S 肽的共结晶，获得了对系链结构的深入了解。通过生成 N 末端到侧链大环以及生成融合大环（双环）的新方法，进一步探索了 ACE 连接肽的范围。总之，这些研究表明 ACE 连接通常适用于肽大环化合物，在合成包含功能标签的稳定螺旋方面具有特定用途。
Macrocyclization is a broadly applied approach for overcoming the intrinsically disordered nature of linear peptides. For example, significant efforts have been developed to stabilize α-helical structures, through tethering proximal side chains. While these approaches successfully mimic protein α-helices, the structural requirements of the tether typically prevent further synthetic modifications to the non-binding face of the helix. Here we demonstrate the utility of dichloroacetone (DCA) to enhance helical secondary structure when introduced between peptide nucleophiles, such as thiols, to yield an acetone (ACE)-linked bridge. In addition to stabilizing helical structures, the ketone moiety embedded into the linker can be modified using oxime ligation with diverse molecular tags. Insights into the structure of the tether were obtained through co-crystallization of a constrained S-peptide in complex with RNAse S. The scope of ACE-linked peptides was further explored through the generation of N-terminus to side chain macrocycles and a new approach for generating fused macrocycles (bicycles). Together, these studies suggest that ACE-linking is generally applicable to peptide macrocycles with a specific utility in the synthesis of stabilized helices that incorporate functional tags.