Conibear Anne C, Thewes Karine, Groysbeck Nadja, Becker Christian F W
Faculty of Chemistry, Institute of Biological Chemistry, University of Vienna, Vienna, Austria.
Front Chem. 2019 Mar 6;7:113. doi: 10.3389/fchem.2019.00113. eCollection 2019.
Chemoselective ligations allow chemical biologists to functionalise proteins and peptides for biomedical applications and to probe biological processes. Coupled with solid phase peptide synthesis, chemoselective ligations enable not only the design of homogeneous proteins and peptides with desired natural and unnatural modifications in site-specific locations but also the design of new peptide and protein topologies. Although several well-established ligations are available, each method has its own advantages and disadvantages and they are seldom used in combination. Here we have applied copper-catalyzed azide-alkyne "click," oxime, maleimide, and native chemical ligations to develop a modular synthesis of branched peptide and polymer constructs that act as cancer-targeting immune system engagers (ISErs) and functionalised them for detection in biological systems. We also note some potential advantages and pitfalls of these chemoselective ligations to consider when designing orthogonal ligation strategies. The modular synthesis and functionalization of ISErs facilitates optimisation of their activity and mechanism of action as potential cancer immunotherapies.
化学选择性连接使化学生物学家能够对蛋白质和肽进行功能化修饰，以用于生物医学应用并探究生物过程。与固相肽合成相结合，化学选择性连接不仅能够设计在特定位置具有所需天然和非天然修饰的均一蛋白质和肽，还能设计新的肽和蛋白质拓扑结构。尽管有几种成熟的连接方法，但每种方法都有其自身的优缺点，并且很少联合使用。在此，我们应用了铜催化的叠氮化物-炔烃“点击”反应、肟反应、马来酰亚胺反应和天然化学连接反应，来开发一种模块化合成方法，用于合成作为癌症靶向免疫系统衔接子（ISErs）的支链肽和聚合物构建体，并对其进行功能化修饰，以便在生物系统中进行检测。我们还指出了这些化学选择性连接在设计正交连接策略时需要考虑的一些潜在优点和陷阱。ISErs的模块化合成和功能化有助于优化其作为潜在癌症免疫疗法的活性和作用机制。
