Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Biomolecules. 2021 Feb 17;11(2):298. doi: 10.3390/biom11020298.
The complement system is part of the innate immune response, where it provides immediate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns offensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and Alzheimer's disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mechanistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.
补体系统是先天免疫反应的一部分，它能提供针对感染原的即时保护，并在维持体内平衡方面发挥着基本作用。补体失调发生在多种疾病中，在这些疾病中，调控严格的蛋白水解级联反应会变得具有攻击性。非典型溶血性尿毒症综合征、阵发性夜间血红蛋白尿和阿尔茨海默病就是突出的例子。针对补体激活的治疗干预可能允许治疗这些使人衰弱的疾病。在这篇综述中，我们描述了一组补体靶向纳米抗体，它们允许在蛋白水解级联的不同步骤进行调节，从经典途径中 C1 复合物的激活到末端途径中 C5 转化酶的形成。彻底的结构和功能表征为每个纳米抗体的抑制模式提供了深入的机制理解。这些补体特异性纳米抗体是基础研究的新型强大探针，并为体内补体调节提供了新的机会。
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