Programa de Ofidismo/Escorpionismo, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín 050010, Colombia.
Institute of Computational Comparative Medicine, Kansas State University, Manhattan, KS 66506, USA.
Molecules. 2018 Oct 16;23(10):2662. doi: 10.3390/molecules23102662.
Most of the snakebite envenomations in Central and South America are caused by species belonging to genus. Their venom is composed mainly by zinc-dependent metalloproteinases, responsible of the hemorrhage characteristic of these envenomations. The aim of this study was to determine the inhibitory ability of ten flavonoids on the in-vitro proteolytic activity of venom and on the hemorrhagic, edema-forming and myonecrotic activities of Batx-I, the most abundant metalloproteinase isolated from this venom. Myricetin was the most active compound, exhibiting an IC 50 value of 150 μ M and 1021 μ M for the inhibition of proteolytic and hemorrhagic activity, respectively. Independent injection experiments, with a concentration of 1600 μ M of myricetin administered locally, immediately after toxin injection, demonstrated a reduction of 28 ± 6 % in the hemorrhagic lesion. Additionally, myricetin at concentrations 800, 1200 and 1600 μ M promoted a reduction in plasma creatine kinase activity induced by Batx-I of 21 ± 2 % , 60 ± 5 % and 63 ± 2 % , respectively. Molecular dynamics simulations coupled with the adaptive biasing method suggest that myricetin can bind to the metalloproteinase active site via formation of hydrogen bonds between the hydroxyl groups 3', 4' and 5' of the benzyl moiety and amino acid Glu143 of the metalloproteinase. The hydroxyl substitution pattern of myricetin appears to be essential for its inhibitory activity. Based on this evidence, myricetin constitutes a candidate for the development of inhibitors to reduce local tissue damage in snakebite envenomations.
中美洲和南美洲的大多数蛇伤是由 属的物种引起的。它们的毒液主要由锌依赖性金属蛋白酶组成，这些蛋白酶负责这些咬伤的出血特征。本研究的目的是确定十种类黄酮对 毒液的体外蛋白水解活性以及 Batx-I（从这种毒液中分离出的最丰富的金属蛋白酶）的出血、水肿形成和肌肉坏死活性的抑制能力。杨梅素是最活跃的化合物，对蛋白水解和出血活性的抑制作用的 IC 50 值分别为 150 μM 和 1021 μM。在毒素注射后立即局部注射 1600 μM 杨梅素的独立注射实验表明，出血病变减少了 28 ± 6%。此外，杨梅素在 800、1200 和 1600 μM 浓度下，分别使 Batx-I 诱导的血浆肌酸激酶活性降低 21 ± 2%、60 ± 5%和 63 ± 2%。分子动力学模拟结合自适应偏置方法表明，杨梅素可以通过苯甲基 3'、4'和 5'位的羟基与金属蛋白酶的Glu143 氨基酸形成氢键，结合到金属蛋白酶的活性部位。杨梅素的羟基取代模式似乎对其抑制活性至关重要。基于这些证据，杨梅素构成了开发抑制剂以减少蛇伤局部组织损伤的候选物。
