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摘要 : 11月16日,自然出版集团旗下综合类刊物《Scientific Reports》在线发表了上海交通大学系统生物医学研究院吴方课题组的一项研究,研究发现天然药物喜得镇或对治疗阿尔茨海默症有疗效。

 11月16日,自然出版集团旗下综合类刊物《Scientific Reports》在线发表了上海交通大学系统生物医学研究院吴方课题组的一项研究,研究发现天然药物喜得镇或对治疗阿尔茨海默症有疗效。硕士研究生雷希岭和于晶老师作为论文第一作者,吴方为论文通讯作者。

随着人类平均寿命的增加,同年龄相关的疾病发病率在逐年升高。阿尔茨海默症(Alzheimer’s Disease,AD)是老年人群中最常见的神经退行性疾病。现在全球约有4400万阿尔茨海默病人。但遗憾的是至今还没有有效控制或减缓阿尔茨海默症发展的特效药。据统计,最近几年针对AD的药物开发的失败率高达99.6%。

上海交通大学系统生物医学研究院吴方课题组通过对417种天然产物进行筛查,发现了一种来自麦角真菌(claviceps purpurea)的天然产物双氢麦角汀可以抑制AD病人细胞致病多肽Abeta的产生。有趣的是,这种天然产物是瑞士诺华公司已上市药物Hydergine®的组分之一。Hydergine®又名喜得镇,于1982年被批准治疗衰老引起的痴呆,但其作用机制不明确,目前尚未在治疗AD上得到广泛应用。



The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer’s disease amyloid-β peptides


Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer’s disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer’s disease.

来源: Scientific Reports 浏览次数:0


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