C5a is an integral glycoprotein of the complement system that plays an important role in inflammation and immunity. The physiological concentration of C5a is observed to be elevated under various immunoinflammatory pathophysiological conditions in humans. The pathophysiology of C5a is linked to the “two-site” protein–protein interactions (PPIs) with two genomically related receptors, such as C5aR1 and C5aR2. Therefore, pharmacophores that can potentially block the PPIs between C5a–C5aR1 and C5a–C5aR2 have tremendous potential for development as future therapeutics. Notably, the FDA has already approved antibodies that target the precursors of C5a (Eculizumab, 148 kDa) and C5a (Vilobelimab, 149 kDa) for marketing as complement-targeted therapeutics. In this context, the current study reports the structural characterization of a pair of synthetic designer antibody-like peptides (DePA and DePA1; ≤3.8 kDa) that bind to hotspot regions on C5a and also demonstrates potential traits to neutralize the function of C5a under pathophysiological conditions.

中文翻译：

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与人类 C5a 结合并具有调节 C5a 受体信号传导潜力的设计抗体样肽的结构


C5a 是补体系统的整合糖蛋白，在炎症和免疫中发挥重要作用。在人类的各种免疫炎症病理生理条件下，观察到 C5a 的生理浓度升高。 C5a 的病理生理学与两个基因组相关受体（例如 C5aR1 和 C5aR2）的“双位点”蛋白质-蛋白质相互作用 (PPI) 有关。因此，能够阻断 C5a-C5aR1 和 C5a-C5aR2 之间 PPI 的药效团作为未来治疗药物具有巨大的开发潜力。值得注意的是，FDA 已批准针对 C5a 前体（Eculizumab，148 kDa）和 C5a（Vilobelimab，149 kDa）的抗体作为补体靶向疗法进行营销。在此背景下，当前的研究报告了一对合成设计抗体样肽（DePA 和 DePA1；≤3.8 kDa）的结构特征，它们与 C5a 上的热点区域结合，并展示了在病理生理学条件下中和 C5a 功能的潜在特征。状况。