Heme binding contributes to antimalarial activity of bis-quaternary ammoniums
Heme binding contributes to antimalarial activity of bis-quaternary ammoniums
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DOI：
10.1128/aac.47.8.2584-2589.2003
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发表时间：
2003-08-01
影响因子：
4.9
通讯作者：
Ward, SA
中科院分区：
文献类型：
--
作者：
Biagini, GA;Richier, E;Ward, SA
季铵盐化合物由于具有抑制新的磷脂酰胆碱合成的能力，在体内具有很强的抗疟疾活性，近年来受到了广泛的关注。在这里，我们表明，除此之外，血红素结合显著有助于这些化合物的抗疟疾活性。在这项研究中，我们使用了最近合成的双季铵化合物T16(1，12-十二烷基亚甲基双[4-甲基-5-乙基噻唑]二碘)，它具有很强的抗疟疾活性(50%的抑制浓度，类似于25 NM)。蓄积分析表明，这种化合物很容易在寄生的红细胞中浓缩几百倍(细胞蓄积率，类似于500)。大约80%的药物分布在寄生虫体内，类似于50%的药物分布在寄生虫的食物液泡中。T16的摄取受到阴离子替代的影响(渗透性按CL-<；bR-=NO3-<；i-<；SCn-的顺序增加)，并对速尿敏感，其性质类似于感染红细胞中诱导新的通透性途径的底物。原位T16结合的Scatchard图分析显示了高亲和力和低亲和力结合位点。高亲和力结合部位K-d与T16和铁原卟啉IX(FPIX)的体外结合部位相似。显著地，降低寄生虫FPIX的浓度会降低高亲和力结合位点的容量，而不是K-d。减少寄生虫的FPIX池也引起对T16抗疟疾活性的明显拮抗。此外，还观察到T16与寄生虫血球蛋白有关。T16与消化食物液泡中的FPIX的结合被证明对药物积累和抗疟疾活性至关重要。这些数据为这类有希望的新的抗疟疾化合物提供了更多的抗疟疾活性的新机制。
Quaternary ammonium compounds have received recent attention due to their potent in vivo antimalarial activity based on their ability to inhibit de novo phosphatidylcholine synthesis. Here we show that in addition to this, heme binding significantly contributes to the antimalarial activity of these compounds. For the study, we used a recently synthesized bis-quaternary ammonium compound, T16 (1,12-dodecanemethylene bis[4-methyl-5-ethylthiazolium] diodide), which exhibits potent antimalarial activity (50% inhibitory concentration, similar to25 nM). Accumulation assays reveal that this compound is readily concentrated several hundredfold (cellular accumulation ratio, similar to500) into parasitized erythrocytes. Approximately 80% of the drug was shown to be distributed within the parasite, similar to50% of which was located in the parasite food vacuoles. T16 uptake was affected by anion substitution (permeation increasing in the order Cl- < Br- = NO3- < I- < SCN-) and was sensitive to furosemide-properties similar to substrates of the induced new permeability pathway in infected erythrocytes. Scatchard plot analysis of in situ T16 binding revealed high-affinity and low-affinity binding sites. The high-affinity binding site K-d was similar to that measured in vitro for T16 and ferriprotoporphyrin IX (FPIX) binding. Significantly, the capacity but not the K-d of the high-affinity binding site was decreased by reducing the concentration of parasite FPIX. Decreasing the parasite FPIX pool also caused a marked antagonism of T16 antimalarial activity. In addition, T16 was also observed to associate with parasite hemozoin. Binding of T16 to FPIX in the digestive food vacuole is shown to be critical for drug accumulation and antimalarial activity. These data provide additional new mechanisms of antimalarial activity for this promising new class of antimalarial compounds.