Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.
Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.
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DOI：
10.7554/elife.10935
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发表时间：
2015-11-18
期刊：
影响因子：
7.7
通讯作者：
Eisenberg DS
中科院分区：
文献类型：
--
作者：
Brumshtein B;Esswein SR;Salwinski L;Phillips ML;Ly AT;Cascio D;Sawaya MR;Eisenberg DS
免疫球蛋白轻链的过量产生导致系统性淀粉样变性，这是一种致命的疾病，其特征是在患者组织中形成淀粉样原纤维。多余的轻链在二聚体和不太稳定的单体之间处于平衡状态，这些单体可以经历不可逆的聚集到淀粉样蛋白状态。因此二聚体必须在形成淀粉样原纤维之前解离成单体。在这里，我们确定了通过稳定Mcg轻链可变结构域二聚体和转移平衡远离淀粉样蛋白倾向单体来抑制淀粉样蛋白形成的配体。DOI: http://dx.doi.org/10.7554/eLife.10935.001系统性轻链淀粉样变性是当个体产生过多的免疫蛋白时发生的疾病。多余的蛋白质链通常以称为“单体”的单个分子或成对的称为“二聚体”的形式存在于体内，它们可以很容易地在这两种形式之间转换。然而，这些单体也容易形成淀粉样原纤维，难以分解。淀粉样蛋白原纤维常沉积在心脏和肾脏，可导致器官衰竭和死亡。发现阻止淀粉样蛋白原纤维形成的分子有助于开发淀粉样变性的治疗方法。现在，Brumshtein， Esswein等人已经筛选了27种化合物，以确定那些稳定蛋白质二聚体形式的化合物。这将减少体内单体的数量，从而减少可以形成淀粉样蛋白原纤维的免疫蛋白的数量。实验确定了四种可以稳定二聚体的化合物，包括一种叫做亚甲基蓝的化合物。将这些化合物的化学结构与批准用于医疗用途的药物的结构进行比较，确定了13种药物。然而，后续的测试表明，只有一种名为柳氮磺胺吡啶的药物能减少淀粉样蛋白原纤维的形成。亚甲蓝和柳氮磺胺嘧啶都不太可能对淀粉样变性有足够强的疗效，但它们可以作为未来药物设计的模板。DOI: http://dx.doi.org/10.7554/eLife.10935.002
Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer. DOI: http://dx.doi.org/10.7554/eLife.10935.001 Systemic light chain amyloidosis is a disease that occurs when individuals produce too much of an immune protein. The excess protein chains normally exist in the body as individual molecules called “monomers” or in pairs called “dimers,” and they can readily switch between these two forms. However, the monomers are also prone to forming amyloid fibrils, which are difficult to break down. Amyloid fibrils are often deposited in the heart and kidneys and can lead to organ failure and death. Finding molecules that prevent the formation of amyloid fibrils could help to develop treatments for amyloidosis. Now, Brumshtein, Esswein et al. have screened 27 compounds to identify those that stabilize the dimer form of the protein. This would reduce the number of monomers in the body, and so reduce the number of immune proteins that can form amyloid fibrils. The experiments identified four compounds that could stabilize the dimers, including one called methylene blue. Comparing the chemical structures of these compounds with the structures of drugs approved for medical use identified thirteen drugs. However, follow-up tests showed that only one, called sulfasalazine, reduced the formation of amyloid fibrils. Neither methylene blue nor sulfasalazine is likely to have a strong enough effect to treat amyloidosis, but they may serve as templates for future drug designs. DOI: http://dx.doi.org/10.7554/eLife.10935.002