当前位置：
X-MOL 学术
›
ACS Chem. Biol.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Identifying the Target of an Antiparasitic Compound in Toxoplasma Using Thermal Proteome Profiling.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-06-29 , DOI: 10.1021/acschembio.0c00369 Alice L Herneisen 1, 2 , Saima M Sidik 2 , Benedikt M Markus 2, 3 , David H Drewry 4, 5 , William J Zuercher 4 , Sebastian Lourido 1, 2
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-06-29 , DOI: 10.1021/acschembio.0c00369 Alice L Herneisen 1, 2 , Saima M Sidik 2 , Benedikt M Markus 2, 3 , David H Drewry 4, 5 , William J Zuercher 4 , Sebastian Lourido 1, 2
Affiliation
|
Apicomplexan parasites include the causative agents of malaria and toxoplasmosis. Cell-based screens in Toxoplasma previously identified a chemical modulator of calcium signaling (ENH1) that blocked parasite egress from host cells and exhibited potent antiparasitic activity. To identify the targets of ENH1, we adapted thermal proteome profiling to Toxoplasma, which revealed calcium-dependent protein kinase 1 (CDPK1) as a target. We confirmed the inhibition of CDPK1 by ENH1 in vitro and in parasites by comparing alleles sensitive or resistant to ENH1. CDPK1 inhibition explained the block in egress; however, the effects of ENH1 on calcium homeostasis and parasite viability were CDPK1-independent, implicating additional targets. Thermal proteome profiling of lysates from parasites expressing the resistant allele of CDPK1 identified additional candidates associated with the mitochondria and the parasite pellicle—compartments that potentially function in calcium release and homeostasis. Our findings illustrate the promise of thermal profiling to identify druggable targets that modulate calcium signaling in apicomplexan parasites.
中文翻译：
使用热蛋白质组分析法鉴定弓形虫中抗寄生虫化合物的靶标。
蚜虫寄生虫包括疟疾和弓形虫病的病原体。弓形虫中基于细胞的筛选先前鉴定出了钙信号传导（ENH1）的化学调节剂，该信号传导剂阻止了寄生虫从宿主细胞中逸出并表现出强大的抗寄生虫活性。为了确定ENH1的目标，我们将热蛋白质组分析应用于弓形虫，它揭示了钙依赖性蛋白激酶1（CDPK1）作为靶标。通过比较对ENH1敏感或耐药的等位基因，我们证实了ENH1在体外和寄生虫中对CDPK1的抑制作用。CDPK1的抑制解释了出口的阻滞。然而，ENH1对钙稳态和寄生虫生存力的影响是CDPK1独立的，牵涉其他目标。从表达CDPK1抗性等位基因的寄生虫的裂解物进行热蛋白质组分析，发现了与线粒体和寄生虫表皮相关的其他候选物-可能在钙释放和体内平衡中起作用的小室。我们的发现说明了通过热分析来鉴定可调节靶标复合体寄生虫中钙信号传导的可药物靶向的前景。
更新日期：2020-07-17
中文翻译：
使用热蛋白质组分析法鉴定弓形虫中抗寄生虫化合物的靶标。
蚜虫寄生虫包括疟疾和弓形虫病的病原体。弓形虫中基于细胞的筛选先前鉴定出了钙信号传导（ENH1）的化学调节剂，该信号传导剂阻止了寄生虫从宿主细胞中逸出并表现出强大的抗寄生虫活性。为了确定ENH1的目标，我们将热蛋白质组分析应用于弓形虫，它揭示了钙依赖性蛋白激酶1（CDPK1）作为靶标。通过比较对ENH1敏感或耐药的等位基因，我们证实了ENH1在体外和寄生虫中对CDPK1的抑制作用。CDPK1的抑制解释了出口的阻滞。然而，ENH1对钙稳态和寄生虫生存力的影响是CDPK1独立的，牵涉其他目标。从表达CDPK1抗性等位基因的寄生虫的裂解物进行热蛋白质组分析，发现了与线粒体和寄生虫表皮相关的其他候选物-可能在钙释放和体内平衡中起作用的小室。我们的发现说明了通过热分析来鉴定可调节靶标复合体寄生虫中钙信号传导的可药物靶向的前景。
京公网安备 11010802027423号