Chen Hao, Zheng Donghang, Davids Jennifer, Bartee Mee Yong, Dai Erbin, Liu Liying, Petrov Lyubomir, Macaulay Colin, Thoburn Robert, Sobel Eric, Moyer Richard, McFadden Grant, Lucas Alexandra
Department of Medicine, Divisions of Cardiovascular Medicine and Rheumatology, University of Florida, Gainesville, Florida, USA.
Methods Enzymol. 2011;499:301-29. doi: 10.1016/B978-0-12-386471-0.00015-8.
Over the past 19 years, we have developed a novel myxoma virus-derived anti-inflammatory serine protease inhibitor, termed a serpin, as a new class of immunomodulatory therapeutic. This review will describe the initial identification of viral serpins with anti-inflammatory potential, beginning with preclinical analysis of viral pathogenesis and proceeding to cell and molecular target analyses, and successful clinical trial. The central aim of this review is to describe the development of two serpins, Serp-1 and Serp-2, as a new class of immune modulating drug, from inception to implementation. We begin with an overview of the approaches used for successful mining of the virus for potential serpin immunomodulators in viruses. We then provide a methodological overview of one inflammatory animal model used to test for serpin anti-inflammatory activity followed by methods used to identify cells in the inflammatory response system targeted by these serpins and molecular responses to serpin treatment. Finally, we provide an overview of our findings from a recent, successful clinical trial of the secreted myxomaviral serpin, Serp-1, in patients with unstable inflammatory coronary arterial disease.
在过去的19年里，我们研发了一种新型的源自黏液瘤病毒的抗炎丝氨酸蛋白酶抑制剂，称为丝氨酸蛋白酶抑制剂（serpin），作为一类新型的免疫调节疗法。本综述将描述具有抗炎潜力的病毒丝氨酸蛋白酶抑制剂的初步鉴定，从病毒发病机制的临床前分析开始，进而进行细胞和分子靶点分析，以及成功的临床试验。本综述的核心目的是描述两种丝氨酸蛋白酶抑制剂Serp-1和Serp-2作为一类新型免疫调节药物从研发到应用的过程。我们首先概述成功从病毒中挖掘潜在丝氨酸蛋白酶抑制剂免疫调节剂所采用的方法。然后，我们提供一种用于测试丝氨酸蛋白酶抑制剂抗炎活性的炎症动物模型的方法概述，接着介绍用于鉴定这些丝氨酸蛋白酶抑制剂在炎症反应系统中靶向的细胞以及丝氨酸蛋白酶抑制剂治疗的分子反应的方法。最后，我们概述了最近在不稳定炎症性冠状动脉疾病患者中对分泌型黏液瘤病毒丝氨酸蛋白酶抑制剂Serp-1进行的成功临床试验的结果。
