2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.
2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.
复制标题
2-十六氰酸抑制疟原虫 FAS-II 酶并阻止红细胞期和肝期疟原虫感染。
DOI：
10.1016/j.bmc.2010.08.055
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发表时间：
2010
影响因子：
3.5
通讯作者：
Carballeira,NéstorM
中科院分区：
文献类型：
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作者：
Tasdemir,Deniz;Sanabria,David;Lauinger,InaL;Tarun,Alice;Herman,Rob;Perozzo,Remo;Zloh,Mire;Kappe,StefanH;Brun,Reto;Carballeira,NéstorM
众所周知，乙炔脂肪酸具有多种生物活性，但其抗疟疾活性尚未得到充分研究。在这项研究中，我们合成了2-、5-、6-和9-hexadecynoic酸（HDAs），并评估了它们对恶性疟原虫红细胞（血液）期和约氏疟原虫肝脏期感染的体外活性。由于II型脂肪酸生物合成途径（PfFAS-II）最近被证明是肝期疟疾寄生虫不可或缺的，因此HDAs对多种恶性疟原虫FAS-II （PfFAS-II）延伸酶的抑制潜力也被评估。在流式细胞检测（ic50值为15.3μg/ml，对照药物阿托伐酮2.5ng/ml）和免疫荧光分析（IC502-HDA 4.88μg/ml，对照药物阿托伐酮0.37ng/ml）中，5-HDA对血期恶性疟原虫的抗疟原虫活性最高（ic50值为6.6μg/ml），而2-HDA是唯一抑制肝期恶性疟原虫生长的酸。2-HDA对PfFAS-II酶PfFabI和PfFabZ的抑制活性最好，ic50值分别为0.38和0.58μg/ml （ic50对照药物14和30ng/ml）。酶动力学和分子模型研究揭示了2-HDA在靶酶上的结合机制。所有hda均对布氏锥虫病（ic50值为3.7 ~ 31.7μg/ml）、锥虫病（ic50值仅为2-HDA， IC5020.2μg/ml）和利什曼多诺瓦氏菌（ic50值为4.1 ~ 13.4μg/ml）具有体外活性，对哺乳动物细胞的毒性一般较低或无显著毒性。这是第一个表明hda对多种寄生原生动物具有治疗潜力的研究。同时指出2-HDA对疟疾肝期生长的抑制作用可能是通过PfFAS-II酶促进的。2-HDA不具有细胞毒性、亲脂性和计算出的药代动力学性质，这表明它可能是研究脂肪酸与这些关键恶性疟原虫酶相互作用的有用化合物。
Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodiumfalciparum and liver stages of Plasmodiumyoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC50value 6.6μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC50value 2-HDA 15.3μg/ml, control drug atovaquone 2.5ng/ml) and immunofluorescence analysis (IC502-HDA 4.88μg/ml, control drug atovaquone 0.37ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC50values of 0.38 and 0.58μg/ml (IC50control drugs 14 and 30ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosomabruceirhodesiense (IC50values 3.7–31.7μg/ml), Trypanosomacruzi (only 2-HDA, IC5020.2μg/ml), and Leishmaniadonovani (IC50values 4.1–13.4μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.