2016年7月11日 讯 /生物谷BIOON/ --最常见的胆固醇药物辛伐他汀对于免疫系统防御相关的疾病，比如1型糖尿病、多发性硬化症及风湿性关节炎具有明显的有益作用，如今来自奥胡斯大学的研究人员就揭示了上述作用发生的原因，相关研究刊登于国际杂志Journal of Biological Chemistry上，该研究或为后期开发治疗慢性炎性疾病的新型疗法提供希望。
正常情况下，免疫防御系统会保护机体免于感染和外来病原体的侵袭，但其有时候会攻击机体的自身组织，目前研究者并不清楚为何免疫系统会发生这样的错误，而免疫系统故障会引发机体处于慢性炎性状态，进而对组织产生损伤作用，并且引发多种疾病，比如风湿性关节炎、多发性硬化症及1型糖尿病。
以多发性硬化症为例，免疫防御系统会破坏中枢神经系统，与此同时炎症就会影响1型和2型糖尿病患者机体的肾脏、眼睛的功能及触觉，从而诱发一系列疾病的发生。然而辛伐他汀被认为可以降低多种疾病中的炎性表现，尽管有时候需要大量摄入这种药物来产生一定效应，但目前研究者并不清楚辛伐他汀的作用原理。
药物辛伐他汀在设计之初并不具有这种效应，如今研究者就揭示了其产生这种效应的一种分子机制，这就为后期开发新型药物抵御多种炎性疾病提供了新的思路，当然研究者们也非常感兴趣致力于此项研究，因为很多人在摄入他汀类药物的同时并不会产生明显的副作用，
药物所扮演的积极作用就是其可以保留机体炎性区域的免疫细胞的功能，这样一来免疫细胞就不会引发炎症产生，从而就有利于患者的日常健康；以糖尿病为例，其可以帮助降低患者患其它并发症的风险。最后研究者Thomas Vorup-Jensen说道，最开始我们在实验室中观察到了这种机制，当然如今我们已经阐明是否药物在体内也可以发挥这样的作用。后期我们还将通过更为深入的研究来探究胆固醇药物对炎性疾病的影响机制。
Structural basis for simvastatin competitive antagonism of complement receptor 3
Maria Risager Jensen1, Goran Bajic1, Xianwei Zhang1, Anne Kjær Laustsen1, Heidi Koldsø1, Katrine Kirkeby Skeby1, Birgit Schiøtt2, Gregers R. Andersen2 and Thomas Vorup-Jensen1*
The complement system is an important part of the innate immune response to infection, but may also cause severe complications during inflammation. Small molecule antagonists to complement receptor (CR)3 have been widely sought, but a structural basis for their mode of action is not available. We report here on the structure of the human CR3 ligand-binding I domain in complex with simvastatin. Simvastatin targets the metal ion-dependent adhesion site of the open, ligand-binding conformation of the CR3 I domain by direct contact with the chelated Mg2+ ion. Simvastatin antagonizes I domain binding to the complement fragments iC3b and C3d, but not to intercellular adhesion molecule-1. By virtue of the I domain's wide distribution in binding kinetics to ligands, it was possible to identify ligand binding kinetics as discriminator for simvastatin antagonism. In static cellular experiments, 15-25 μM simvastatin reduced adhesion by K562 cells expressing recombinant CR3 and by primary human monocytes, with an endogenous expression of this receptor. Application of force to adhering monocytes potentiated the effects of simvastatin where only 50-100 nM of the drug reduced the adhesion with 20-40% compared with untreated cells. The ability of simvastatin to target CR3 in its ligand binding-activated conformation is a novel mechanism to explain the known anti-inflammatory effects of this compound, in particular as this CR3 conformation is found in pro-inflammatory environments. Our report points to new designs of CR3 antagonists and opens new perspectives and identifies druggable receptors from characterization of the ligand binding kinetics in the presence of antagonists.