鞣花酸的抗锥虫作用及其对锥虫相关病理特征的改善作用，以及对锥虫唾液酸酶的体外和计算机抑制作用。
Trypanosuppresive effects of ellagic acid and amelioration of the trypanosome-associated pathological features coupled with inhibitory effects on trypanosomal sialidase in vitro and in silico.
机构信息
Department of Biochemistry, Ahmadu Bello University, Zaria, Nigeria.
Department of Biochemistry, Ahmadu Bello University, Zaria, Nigeria.
出版信息
Phytomedicine. 2017 Jul 1;30:67-73. doi: 10.1016/j.phymed.2017.04.013. Epub 2017 May 2.
BACKGROUND
The search for novel antitrypanosomal agents had previously led to the isolation of ellagic acid as a bioactive antitrypanosomal compound using in vitro studies. However, it is not known whether this compound will elicit antitrypanosomal activity in in vivo condition which is usually the next step in the drug discovery process.
PURPOSE
Herein, we investigated the in vivo activity of ellagic acid against bloodstream form of Trypanosoma congolense and its ameliorative effects on trypanosome-induced anemia and organ damage as well as inhibitory effects on trypanosomal sialidase.
METHODS
Rats were infected with T. congolense and were treated with 100 and 200mg/kg body weight (BW) of ellagic acid for fourteen days. The levels of parasitemia, packed cell volume and biochemical parameters were measured. Subsequently, T. congolense sialidase was partially purified on DEAE cellulose column and the mode of inhibition of ellagic acid on the T. congolense sialidase determined. Molecular docking study was also conducted to determine the mode of interaction of the ellagic acid to the catalytic domain of T. rangeli sialidase.
RESULTS
At a dose of 100 and 200mg/kg (BW), ellagic acid demonstrated significant (P < 0.05) trypanosuppressive effect for most of the 24 days experimental period. Further, the ellagic acid significantly (P < 0.05) ameliorated the trypanosome-induced anemia, hepatic and renal damages as well as hepatomegaly, splenomegaly and renal hypertrophy. The trypanosome-associated free serum sialic acid upsurge alongside the accompanied membrane bound sialic acid reduction were also significantly (P < 0.05) prevented by the ellagic acid treatment. The T. congolense sialidase was purified to a fold of 6.6 with a yield of 83.8%. The enzyme had a K and Vmax of 70.12mg/ml and 0.04µmol/min respectively, and was inhibited in a non-competitive pattern by ellagic acid with an inhibition binding constant of 1986.75μM. However, in molecular docking study, ellagic acid formed hydrogen bonding interaction with major residues R, R, and W at the active site of T. rangeli sialidase with a predicted binding free energy of -25.584kcal/mol.
CONCLUSION
We concluded that ellagic acid possesses trypanosuppressive effects and could ameliorate the trypanosome-induced pathological alterations.
背景
先前的寻找新型抗锥虫药物的研究，已经从体外研究中分离出鞣花酸作为一种具有抗锥虫活性的化合物。然而，鞣花酸是否会在体内条件下产生抗锥虫活性，这通常是药物发现过程的下一步，目前还不得而知。
目的
本文研究了鞣花酸对刚果锥虫血液期的体内活性及其对锥虫引起的贫血和器官损伤的改善作用，以及对锥虫唾液酸酶的抑制作用。
方法
用刚果锥虫感染大鼠，用 100 和 200mg/kg 体重（BW）的鞣花酸治疗 14 天。测量寄生虫血症、红细胞压积和生化参数。随后，用 DEAE 纤维素柱对 T. congolense 唾液酸酶进行部分纯化，并确定鞣花酸对 T. congolense 唾液酸酶的抑制模式。还进行了分子对接研究，以确定鞣花酸与 T. rangeli 唾液酸酶催化结构域的相互作用模式。
结果
鞣花酸在 100 和 200mg/kg（BW）剂量下，在实验的大部分 24 天期间对锥虫具有显著的（P < 0.05）抑制作用。此外，鞣花酸还显著（P < 0.05）改善了锥虫引起的贫血、肝肾功能损伤以及肝肿大、脾肿大和肾肥大。鞣花酸治疗还显著（P < 0.05）阻止了锥虫相关的游离血清唾液酸的增加以及伴随的膜结合唾液酸的减少。刚果锥虫唾液酸酶被纯化到 6.6 倍，收率为 83.8%。该酶的 K 和 Vmax 分别为 70.12mg/ml 和 0.04µmol/min，以非竞争性模式被鞣花酸抑制，抑制结合常数为 1986.75μM。然而，在分子对接研究中，鞣花酸与 T. rangeli 唾液酸酶的活性位点上的主要残基 R、R 和 W 形成氢键相互作用，预测结合自由能为-25.584kcal/mol。
结论
我们得出结论，鞣花酸具有抗锥虫作用，并能改善锥虫引起的病理改变。
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