Myeloperoxidase Inhibitors as Potential Drugs
Myeloperoxidase Inhibitors as Potential Drugs
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DOI：
10.2174/138920021603150812120640
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发表时间：
2015-01-01
影响因子：
2.3
通讯作者：
Vasic, Vesna
中科院分区：
文献类型：
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作者：
Lazarevic-Pasti, Tamara;Leskovac, Andreja;Vasic, Vesna
髓过氧化物酶（MPO）是血红素过氧化物酶-环氧合酶超家族的重要成员.这种酶在生理学上在循环中性粒细胞、单核细胞和一些组织巨噬细胞（包括小胶质细胞）中表达。MPO在人类的抗微生物和抗病毒系统中起着至关重要的作用。MPO的杀微生物活性的存在是由于其通过H2 O2氧化卤化物和拟卤化物离子（Cl-、Br-、I-和SCN-）的能力，从而产生相应的次卤酸（HOX）。在病原体的吞噬过程中，嗜天青颗粒将其内容物与MPO一起释放到吞噬溶酶体中。另一方面，MPO可被排出吞噬细胞外。因此，MPO衍生的氧化剂极大地促进了炎症期间的组织损伤。就其活性而言，MPO是心血管疾病、炎性疾病、神经退行性疾病、肾脏疾病和免疫介导的疾病组中的大量病症的关键因素。因此，MPO及其下游炎症通路可能是预防所有上述疾病的预后和治疗干预的有吸引力的靶点。目前，MPO的结构和反应机制已被人们所了解，这使得开发特异性MPO抑制剂的策略变得合理，这些抑制剂在宿主防御细菌的过程中仍然保持MPO活性，但在病理生理学上阻止MPO的持续活化。将讨论MPO活性抑制的各种方法和MPO衍生的氧化剂重塑的不利影响。重点将放在各种已知的抑制剂，以及对新研究的天然产物，这也可以抑制MPO活性。
Myeloperoxidase (MPO) is an important member of the haem peroxidase - cyclooxygenase superfamily. This enzyme is physiologically expressed in circulating neutrophils, monocytes and some tissue macrophages including microglia. MPO plays an essential role in the antimicrobial and antiviral system of humans. The microbicidal activity of MPO exists due to its capability to oxidize halide and pseudohalide ions (Cl-, Br-, I- and SCN-) by H2O2, thereby producing respective hypohalous acids (HOX). During the phagocytosis of pathogens, azurophilic granules release their content together with MPO into phagolysosomes. On the other hand, MPO can be discharged outside the phagocytes. Due to this, tissue damage during inflammation is greatly promoted by MPO-derived oxidants. Regarding its activity, MPO is a key factor in a great number of conditions within the group of cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, kidney diseases and immune-mediated diseases. Therefore, MPO and its downstream inflammatory pathways might be attractive targets for both prognostic and therapeutic intervention in the prophylaxis of all mentioned illnesses. Nowadays, structure and reaction mechanism of MPO are known, which enable rational strategy in the development of specific MPO inhibitors that still preserve MPO activity during host defense from bacteria, but hinder pathophysiologically persistent activation of MPO. Various methods for MPO activity inhibition and unfavorable effects of MPO-derived oxidants remodeling will be discussed. Emphasis will be put on various known inhibitors, as well as on newly investigated natural products, which can also inhibit MPO activity.