Istituto di Biostrutture e Bioimmagini-CNR, Naples, Italy.
Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Universita degli Studi di Firenze, Sesto Fiorentino, Florence, Italy.
Curr Med Chem. 2018;25(39):5266-5278. doi: 10.2174/0929867325666180326160121.
Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.
属于疟原虫、利什曼原虫和锥虫属的原生动物会引起广泛的寄生虫病，这些疾病的治疗选择很少，而且许多临床使用的药物都经历了广泛的耐药现象。在过去的几年中，金属酶碳酸酐酶（CA，EC 4.2.1.1）在这些原生动物的基因组中被克隆和表征，目的是寻找治疗疟疾、利什曼病和恰加斯病的新药物靶点。恶性疟原虫编码一种属于新型遗传家族的 CA（PfCA），η-CA 类，L. donovani chagasi 为β-CA（LdcCA），而 T. cruzi 基因组则包含α-CA（TcCA）。这些三种酶都被详细地进行了特征描述，发现了许多属于磺胺类、硫醇类、二硫代氨基甲酸盐类和羟肟酸类的体外高效和选择性抑制剂。其中一些抑制剂在原生动物感染的细胞培养物和动物模型中也具有疗效，这使得它们具有相当大的潜力，可以开发具有新型作用机制的新型抗原生动物药物。
