Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Adv Exp Med Biol. 2013;735:23-40. doi: 10.1007/978-1-4614-4118-2_2.
Proteases play important roles in human physiology and pathology. The complement system is a proteolytic cascade, where serine proteases activate each other by limited proteolysis in a strictly ordered manner. Serine proteases are essential in both the initiation and the amplification of the cascade. Since uncontrolled complement activation contributes to the development of serious disease conditions, inhibition of the complement serine proteases could be an attractive therapeutic approach. In this chapter, we give a brief overview of the major types of natural serine protease inhibitors and their role in controlling the complement cascade. A special emphasis is laid on C1-inhibitor, a natural complement protease inhibitor, which is approved for clinical use in hereditary angioedema (HAE). We also examine the potential of developing artificial complement protease inhibitors. Synthetic small-molecule drugs can be very efficient serine protease inhibitors, but they usually lack sufficient specificity. A promising approach to yield more specific compounds is the alteration of natural protease inhibitors through engineering or directed evolution resulting in new variants with fine-tuned specificity and enhanced affinity.
蛋白酶在人类生理和病理中发挥着重要作用。补体系统是一个蛋白水解级联反应，其中丝氨酸蛋白酶通过有限的蛋白水解以严格有序的方式相互激活。丝氨酸蛋白酶在级联反应的启动和放大中都是必不可少的。由于补体的不受控制的激活会导致严重疾病的发展，因此抑制补体丝氨酸蛋白酶可能是一种有吸引力的治疗方法。在本章中，我们简要概述了主要类型的天然丝氨酸蛋白酶抑制剂及其在控制补体级联反应中的作用。特别强调了 C1 抑制剂，它是一种天然的补体蛋白酶抑制剂，已被批准用于遗传性血管性水肿（HAE）的临床治疗。我们还研究了开发人工补体蛋白酶抑制剂的潜力。合成的小分子药物可以是非常有效的丝氨酸蛋白酶抑制剂，但它们通常缺乏足够的特异性。一种很有前途的方法是通过工程或定向进化来改变天然蛋白酶抑制剂，从而产生具有精细调节特异性和增强亲和力的新变体。
