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首页> 外文期刊>Biochemistry >Identification and Characterization of Allophenylnorstatine-Based Inhibitors of Plasmepsin II, an Antimalarial Target
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Identification and Characterization of Allophenylnorstatine-Based Inhibitors of Plasmepsin II, an Antimalarial Target

机译：识别和表征基于别苯基去甲他汀的纤溶酶II抑制剂（抗疟疾靶标）

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摘要

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II with a K_i of 70 nM and a 22-fold selectivity with respect to the highly homologous human enzyme cathepsin D.KNI-727 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 deg C, t he binding enthalpy (#DELTA#H) is -4.4 kcal/mol and the entropic contribution (-T#DELTA#S) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 deg C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the malaria parasite was validated by performing cytotoxicity assays in red blood cells infected with Plasmodium falciparum. EC_(50S) ranging between 6 and 10 #mu#M (3-6#mu#g/mL) were obtained. These experiments demonstrate the viability of the allophenylnorsatine scaffold in the design of powerful and selective plasmepsin inhibitors.
机译：纤溶酶II是疟原虫寄生虫生命周期中的关键酶，疟疾是一种疟疾，每年折磨3亿多人。由于纤溶酶II的抑制导致寄生虫的饥饿，因此已被认为是开发新抗疟疾药物的重要目标。在本文中，我们基于别苯基去甲他汀骨架，鉴定并鉴定了纤溶酶II的高亲和力抑制剂。最好的化合物，KNI-727，基于别苯基去甲他汀骨架，可抑制纤溶酶II。最好的化合物KNI-727以70 nM的K_i抑制纤溶酶II，相对于高度同源的人类组织蛋白酶D的选择性是22倍.KNI-727在热和熵过程中均与纤溶酶II结合。在25摄氏度时，结合焓（＃DELTA＃H）为-4.4 kcal / mol，对吉布斯能量的熵贡献（-T＃DELTA＃S）为-5.56 kcal / mol。纤溶酶II的结构稳定性测量也用于表征抑制剂结合。在没有抑制剂的情况下进行的高灵敏度差示扫描量热法实验表明，在pH 4.0时，纤溶酶II在63.3℃下发生热变性。酶的结构稳定性随抑制剂浓度的增加而增加，其结合能抑制剂可以定量说明。通过在恶性疟原虫感染的红细胞中进行细胞毒性分析，验证了最佳化合物杀死疟原虫的有效性。获得的EC_（50S）为6至10＃mu＃M（3-6＃mu＃g / mL）。这些实验证明了别苯基诺莎汀支架在设计有效的选择性纤溶酶抑制剂中的可行性。

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