Pharmacognosy, Bioanalysis and Drug Discovery, Research in Drug Development, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Department of Chemistry, Institute of Biochemistry, University of Natural Resources and Life Sciences, Vienna, Austria.
Handb Exp Pharmacol. 2021;264:261-285. doi: 10.1007/164_2020_388.
Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. This has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, based on the profound knowledge of structure and function of MPO and its biochemical and biophysical differences with the other homologous human peroxidases, various rational and high-throughput screening attempts were performed in developing specific irreversible and reversible inhibitors. The most prominent candidates as well as MPO inhibitors already studied in clinical trials are introduced and discussed.
髓过氧化物酶通过形成杀菌性的活性氧和可扩散自由基参与先天免疫防御机制。其独特的活性是能够利用氯化物作为过氧化氢的共底物，生成次氯酸等氯化氧化剂，这是一种有效的抗菌剂。然而，慢性 MPO 激活可导致无差别蛋白质修饰，引起组织损伤，并与慢性炎症性疾病、动脉粥样硬化和急性心血管事件有关。这引起了人们对开发治疗上有用的 MPO 抑制剂的极大兴趣。如今，基于对 MPO 的结构和功能及其与其他同源人过氧化物酶的生化和生物物理差异的深入了解，人们进行了各种合理的高通量筛选尝试，以开发特异性的不可逆和可逆抑制剂。本文介绍和讨论了作为最显著候选物以及已经在临床试验中研究过的 MPO 抑制剂。
