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首页> 外文期刊>Biochemistry >Inhibition by Flavonoids of Amyloid-like Fibril Formationby Plasmodium falcipanun Merozoite Surface Protein 2
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Inhibition by Flavonoids of Amyloid-like Fibril Formationby Plasmodium falcipanun Merozoite Surface Protein 2

机译：类黄酮对恶性疟原虫裂殖子表面蛋白2的淀粉样样原纤维形成的抑制作用。

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Merozoite surface protein 2 (MSP2) is a glycosylphosphatidylinositol (GPI)-anchore protein expressed abundantly on the surface of Plasmodium falciparum merozoites. The results of a phase 2 trial in Papua New Guinean children showed MSP2 to be a promising malaria vaccine candidate. MSP2 is intrin-sically unstructured and forms amyloid-like fibrils under physiological conditions. Oligomers containing β-strand interactions similar to those in amyloid fibrils may be a component of the fibrillar surface coat on P. falciparum merozoites. As the propensity of MSP2 to form fibrils in solution also has the potential to impede its development as a vaccine candidate, finding an inhibitor that specifically inhibits fibrillogenesis may enhance vaccine development. In this study, we tested the ability of three flavonoids. EGCG, baicalein, and resveratrol, to inhibit MSP2 fibrillogenesis and found marked inhibition with EGCG but not 'kith the other two flavonoids. The inhibitory effect and the interactions of the flavonoids with MSP2 were character-ized using NMR spectroscopy, thioflavin T fluorescence assays, electron microscopy, and other biophysical methods. EGCG stabilizes soluble oligomers and blocks fibrillogenesis by preventing the conformational transition of MSP2 from a random coil to an amyloidogenic β-sheet structure. Structural comparison of the three flavonoids indicates an association between their propensity for autoxidation and their fibril inhibitory activity; the activity of EGCG can be attributed to the vicinal hydroxyl groups present in this flavonoid and their ability to form quinones. The molecular mechanism of fibril inhibition by EGCG appears to be complex and involves noncovalent binding followed by covalent modification of the protein. Although the addition of EGCG appears to be an effective means of stabilizing MSP2 in solution, the covalent modification of MSP2 would most likely not be acceptable in a vaccine formulation. However, these small molecule inhibitors of MSP2 fibril formation will he useful as mechanistic probes in studying oligomerization and fibril assembly of MSP2.
机译：裂殖子表面蛋白2（MSP2）是在恶性疟原虫裂殖子表面上大量表达的糖基磷脂酰肌醇（GPI）-锚定蛋白。在巴布亚新几内亚儿童中进行的2期试验结果表明，MSP2是有希望的疟疾疫苗候选者。 MSP2本质上是非结构化的，在生理条件下会形成淀粉样蛋白原纤维。含有与淀粉样蛋白原纤维相似的β-链相互作用的寡聚体可能是恶性疟原虫裂殖子上原纤维表面涂层的成分。由于MSP2在溶液中形成原纤维的倾向也有可能阻碍其作为候选疫苗的发展，因此找到能特异性抑制原纤维形成的抑制剂可能会促进疫苗的开发。在这项研究中，我们测试了三种类黄酮的能力。 EGCG，黄ical素和白藜芦醇可抑制MSP2的原纤维形成，并被EGCG显着抑制，但不能抑制另外两种黄酮类化合物。使用NMR光谱，硫代黄素T荧光测定，电子显微镜和其他生物物理方法表征了类黄酮与MSP2的抑制作用和相互作用。 EGCG通过防止MSP2从无规卷曲到淀粉样蛋白形成的β-折叠结构的构象转变，稳定了可溶性低聚物并阻止了原纤维形成。三种黄酮类化合物的结构比较表明，它们的自氧化倾向与原纤维抑制活性之间存在关联。 EGCG的活性可以归因于该类黄酮中存在的邻位羟基及其形成醌的能力。 EGCG抑制原纤维的分子机制似乎很复杂，涉及非共价结合，随后是蛋白质的共价修饰。尽管添加EGCG似乎是稳定溶液中MSP2的有效方法，但是MSP2的共价修饰在疫苗制剂中极有可能是不可接受的。但是，这些MSP2原纤维形成的小分子抑制剂将用作研究MSP2寡聚和原纤维组装的机制探针。

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