Department of Medicine, University of Florida, Gainesville, FL 32610-0277, USA.
Adv Exp Med Biol. 2009;666:132-56. doi: 10.1007/978-1-4419-1601-3_11.
Serine proteinase inhibitors, also called serpins, are an ancient grouping of proteins found in primitive organisms from bacteria, protozoa and horseshoe crabs and thus likely present at the time of the dinosaurs, up to all mammals living today. The innate or inflammatory immune system is also an ancient metazoan regulatory system, providing the first line of defense against infection or injury. The innate inflammatory defense response evolved long before acquired, antibody dependent immunity. Viruses have developed highly effective stratagems that undermine and block a wide variety of host inflammatory and immune responses. Some of the most potent of these immune modifying strategies utilize serpins that have also been developed over millions of years, including the hijacking by some viruses for defense against host immune attacks. Serpins represent up to 2-10 percent of circulating plasma proteins, regulating actions as wide ranging as thrombosis, inflammation, blood pressure control and even hormone transport. Targeting serpin-regulated immune or inflammatory pathways makes evolutionary sense for viral defense and many of these virus-derived inhibitory proteins have proven to be highly effective, working at very low concentrations--even down to the femptomolar to picomolar range. We are studying these viral anti-inflammatory proteins as a new class of immunomodulatory therapeutic agents derived from their native viral source. One such viral serpin, Serp-1 is now in clinical trial (conducted by VIRON Therapeutics, Inc.) for acute unstable coronary syndromes (unstable angina and small heart attacks), representing a 'first in class' therapeutic study. Several other viral serpins are also currently under investigation as anti-inflammatory or anti-immune therapeutics. This chapter describes these original studies and the ongoing analysis of viral serpins as a new class of virus-derived immunotherapeutic.
丝氨酸蛋白酶抑制剂，也称为丝氨酸蛋白酶抑制剂，是一种古老的蛋白质群，存在于细菌、原生动物和马蹄蟹等原始生物中，因此可能存在于恐龙时代，甚至存在于今天所有的哺乳动物中。先天或炎症性免疫系统也是一种古老的后生动物调节系统，为抵御感染或损伤提供第一道防线。先天炎症防御反应是在获得性、抗体依赖性免疫之前很久就进化而来的。病毒已经开发出了非常有效的策略，破坏和阻止宿主的各种炎症和免疫反应。其中一些最有效的免疫调节策略利用了丝氨酸蛋白酶抑制剂，这些抑制剂也已经进化了数百万年，包括一些病毒利用丝氨酸蛋白酶抑制剂来防御宿主的免疫攻击。丝氨酸蛋白酶抑制剂占循环血浆蛋白的 2-10%，调节的作用范围广泛，包括血栓形成、炎症、血压控制甚至激素转运。针对丝氨酸蛋白酶抑制剂调节的免疫或炎症途径，对于病毒防御来说具有进化意义，许多这些源自病毒的抑制蛋白已被证明是非常有效的，在非常低的浓度下发挥作用，甚至低至飞摩尔到皮摩尔范围。我们正在研究这些病毒抗炎蛋白，作为一种源自其天然病毒来源的新型免疫调节治疗药物。一种这样的病毒丝氨酸蛋白酶抑制剂 Serp-1 目前正在进行临床试验（由 VIRON Therapeutics, Inc. 进行），用于治疗急性不稳定型冠状动脉综合征（不稳定型心绞痛和小面积心肌梗死），这是一项“同类首创”的治疗研究。其他几种病毒丝氨酸蛋白酶抑制剂也正在作为抗炎或免疫治疗药物进行研究。本章描述了这些原始研究以及作为一种新型病毒衍生免疫治疗药物的病毒丝氨酸蛋白酶抑制剂的持续分析。
