Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Front Immunol. 2018 Aug 8;9:1851. doi: 10.3389/fimmu.2018.01851. eCollection 2018.
The complement system has moved into the focus of drug development efforts in the last decade, since its inappropriate or uncontrolled activation has been recognized in many diseases. Some of them are primarily complement-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, and atypical hemolytic uremic syndrome. Complement also plays a role in various multifactorial diseases that affect millions of people worldwide, such as ischemia reperfusion injury (myocardial infarction, stroke), age-related macular degeneration, and several neurodegenerative disorders. In this review, we summarize the potential advantages of targeting various complement proteins with special emphasis on the components of the lectin (LP) and the alternative pathways (AP). The serine proteases (MASP-1/2/3, factor D, factor B), which are responsible for the activation of the cascade, are straightforward targets of inhibition, but the pattern recognition molecules (mannose-binding lectin, other collectins, and ficolins), the regulatory components (factor H, factor I, properdin), and C3 are also subjects of drug development. Recent discoveries about cross-talks between the LP and AP offer new approaches for clinical intervention. Mannan-binding lectin-associated serine proteases (MASPs) are not just responsible for LP activation, but they are also indispensable for efficient AP activation. Activated MASP-3 has recently been shown to be the enzyme that continuously supplies factor D (FD) for the AP by cleaving pro-factor D (pro-FD). In this aspect, MASP-3 emerges as a novel feasible target for the regulation of AP activity. MASP-1 was shown to be required for AP activity on various surfaces, first of all on LPS of Gram-negative bacteria.
补体系统在过去十年中成为药物开发的焦点，因为人们已经认识到其不适当或不受控制的激活与许多疾病有关。其中一些疾病主要是补体介导的罕见疾病，如阵发性夜间血红蛋白尿、C3 肾小球肾炎和非典型溶血尿毒症综合征。补体在许多影响全球数百万人的多因素疾病中也发挥作用，如缺血再灌注损伤（心肌梗死、中风）、年龄相关性黄斑变性和几种神经退行性疾病。在这篇综述中，我们总结了靶向各种补体蛋白的潜在优势，特别强调了凝集素（LP）和替代途径（AP）的组成部分。丝氨酸蛋白酶（MASPs-1/2/3、因子 D、因子 B）负责级联激活，是抑制的直接靶点，但模式识别分子（甘露聚糖结合凝集素、其他 collectins 和 ficolin）、调节成分（因子 H、因子 I、properdin）和 C3 也是药物开发的对象。LP 和 AP 之间的串扰的最新发现为临床干预提供了新的方法。甘露聚糖结合凝集素相关丝氨酸蛋白酶（MASPs）不仅负责 LP 激活，而且对于 AP 激活也是必不可少的。最近发现激活的 MASP-3 通过切割原因子 D（pro-FD），为 AP 不断提供因子 D（FD）。在这方面，MASP-3 作为调节 AP 活性的新的可行靶点出现。MASP-1 被证明在各种表面上都需要 AP 活性，首先是革兰氏阴性菌的 LPS。
