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皮埃里康 A 和 B 作为强效抗血栓剂:具有意想不到的化学结构的纳米分子非竞争性蛋白质二硫化物异构酶抑制剂

Guijuan Zheng¹, Keyu Lv², Hao Wang²

¹Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China.

Journal of the American Chemical Society

|January 25, 2023

概括

从Pieris japonica中发现了四种新的化合物,即piericones A-D,并被确定为细胞外蛋白二硫化异构酶 (PDI) 的强有力的抑制剂. 通过抑制血栓形成而不会增加出血风险,Piericone A对结血性疾病的治疗具有前景.

科学领域:

自然产品化学
医学化学
生物化学

背景情况:

细胞外蛋白二硫化异构酶 (PDI) 是血栓性疾病的关键因素.
开发针对PDI的抑制剂为这些疾病提供了治疗策略.

研究的目的:

从自然来源中分离和描述新的PDI抑制剂.
评估这些抑制剂的抗血栓作用.

主要方法:

使用光谱数据,化学方法,量子NMR,ECD计算和X射线结晶学来分离和阐明piericones A-D的结构.
生物化学测试以确定PDI抑制动力学.
在体外和体内的抗血栓活性评估.
分子对接和动力学模拟.

主要成果:

四种新的化合物,piericones A-D,是从Pieris japonica中分离出来的.
皮埃里康 A 和 B 是强大的非竞争性 PDI 抑制剂,具有独特的化学结构和九个固态中心.
通过向细胞外PDI,Piericone A显著抑制了血小板聚合,纤维素形成和体内血栓形成.
没有观察到Piericone A治疗增加的出血风险.
分子模拟为piericones A和B的结合机制提供了洞察力.

结论:

皮埃里康 A-D 是一种具有前所未有的架构的新型PDI抑制剂.
皮埃里康A具有强大的抗血栓活性和良好的安全性,使其成为进一步药物开发的有希望的候选药物.
这项研究为设计新型PDI抑制剂作为抗血栓剂提供了结构基础.

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