Babesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril.
Babesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril.
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DOI：
10.1016/j.jbc.2023.105313
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发表时间：
2023-11
期刊：
影响因子：
--
通讯作者：
Ben Mamoun C
中科院分区：
文献类型：
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作者：
Vydyam P;Choi JY;Gihaz S;Chand M;Gewirtz M;Thekkiniath J;Lonardi S;Gennaro JC;Ben Mamoun C
用于治疗由红细胞内寄生虫引起的疾病的有效且安全的疗法由于耐药性的快速出现和缺乏新的药物靶点而受到阻碍。其中一种疾病是人类巴贝斯虫病，这是一种由巴贝斯虫寄生虫引起的迅速出现的蜱传疾病。在这项研究中，我们确定了福辛普利，一种含膦酸盐，FDA批准的血管紧张素转换酶（ACE）抑制剂，通常用作高血压和心力衰竭的前药，作为一种有效的抑制剂，在人类红细胞内的邓肯巴氏疟原虫的发展。细胞生物学和质谱分析表明，福辛普利转化为其活性二酸分子福辛普利拉是其抗寄生虫活性所必需的。我们表明，这种转换是由寄生虫编码的酯酶，BdFE1，这是高度保守的顶复门寄生虫。在BdFE 1的活性位点携带L238H突变的寄生虫未能将前药转化为其活性部分，并对药物产生耐药性。我们的数据为开发这类药物治疗媒介传播的寄生虫病奠定了基础。
Effective and safe therapies for the treatment of diseases caused by intraerythrocytic parasites are impeded by the rapid emergence of drug resistance and the lack of novel drug targets. One such disease is human babesiosis, which is a rapidly emerging tick-borne illness caused by Babesia parasites. In this study, we identified fosinopril, a phosphonate-containing, FDA-approved angiotensin converting enzyme (ACE) inhibitor commonly used as a prodrug for hypertension and heart failure, as a potent inhibitor of Babesia duncani parasite development within human erythrocytes. Cell biological and mass spectrometry analyses revealed that the conversion of fosinopril to its active diacid molecule, fosinoprilat, is essential for its antiparasitic activity. We show that this conversion is mediated by a parasite-encoded esterase, BdFE1, which is highly conserved among apicomplexan parasites. Parasites carrying the L238H mutation in the active site of BdFE1 failed to convert the prodrug to its active moiety and became resistant to the drug. Our data set the stage for the development of this class of drugs for the therapy of vector-borne parasitic diseases.