Viviana De Luca, Simone Giovannuzzi, Clemente Capasso, Claudiu T Supuran
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引用次数: 0
摘要
由细胞内寄生虫弓形虫诱发的弓形虫病对全球健康具有重大影响。虽然主要针对叶酸途径酶的治疗方案有明显的局限性,但目前的研究工作主要集中在确定对寄生虫生存至关重要的特定代谢途径上。由于碳酸酐酶(CAs,EC 4.2.1.1)在对各种原生动物代谢过程至关重要的基本反应中的作用,它们已成为潜在的药物靶点。在淋球菌中,碳酸酐酶相关蛋白(TgCA_RP)在跳虫的生物发生过程中发挥着关键作用。值得注意的是,来自另一种原生动物克氏锥虫的α-CA(TcCA)对阴离子、磺酰胺类、硫醇类和羟酰胺类等经典 CA 抑制剂(CAIs)表现出相当大的敏感性。本文采用 DNA 重组技术合成并克隆了克鲁兹锥虫基因组中已确定的编码 α-CA 蛋白(Tg_CA)的基因,目的是异源过表达其相应的蛋白。测定了 Tg_CA 的动力学常数,并探索了其与无机金属络合化合物的抑制模式,这对合理设计化合物具有重要意义。这项研究的意义在于有可能开发出创新的治疗策略,破坏对淋球菌的生存和毒力至关重要的代谢途径。这项研究可能会开发出有针对性的治疗方法,为控制弓形虫病提供新的途径。
Cloning, expression, and purification of an α-carbonic anhydrase from Toxoplasma gondii to unveil its kinetic parameters and anion inhibition profile.
Toxoplasmosis, induced by the intracellular parasite Toxoplasma gondii, holds considerable implications for global health. While treatment options primarily focusing on folate pathway enzymes have notable limitations, current research endeavours concentrate on pinpointing specific metabolic pathways vital for parasite survival. Carbonic anhydrases (CAs, EC 4.2.1.1) have emerged as potential drug targets due to their role in fundamental reactions critical for various protozoan metabolic processes. Within T. gondii, the Carbonic Anhydrase-Related Protein (TgCA_RP) plays a pivotal role in rhoptry biogenesis. Notably, α-CA (TcCA) from another protozoan, Trypanosoma cruzi, exhibited considerable susceptibility to classical CA inhibitors (CAIs) such as anions, sulphonamides, thiols, and hydroxamates. Here, the recombinant DNA technology was employed to synthesise and clone the identified gene in the T. gondii genome, which encodes an α-CA protein (Tg_CA), with the purpose of heterologously overexpressing its corresponding protein. Tg_CA kinetic constants were determined, and its inhibition patterns explored with inorganic metal-complexing compounds, which are relevant for rational compound design. The significance of this study lies in the potential development of innovative therapeutic strategies that disrupt the vital metabolic pathways crucial for T. gondii survival and virulence. This research may lead to the development of targeted treatments, offering new approaches to manage toxoplasmosis.
期刊介绍:
Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents.
Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research.
The journal’s focus includes current developments in:
Enzymology;
Cell biology;
Chemical biology;
Microbiology;
Physiology;
Pharmacology leading to drug design;
Molecular recognition processes;
Distribution and metabolism of biologically active compounds.