Institute of Biomedical Technology, Fimlab Ltd, School of Medicine and BioMediTech, University of Tampere and Tampere University Hospital, Medisiinarinkatu 3, 33520 Tampere, Finland.
Bioorg Med Chem. 2013 Aug 1;21(15):4472-6. doi: 10.1016/j.bmc.2013.05.058. Epub 2013 Jun 6.
The protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease, encodes an α-class carbonic anhydrase (CA, EC 4.2.1.1), TcCA, which was recently shown to be crucial for its life cycle. Thiols, a class of strong TcCA inhibitors, were also shown to block the growth of the pathogen in vitro. Here we report the inhibition of TcCA by inorganic and complex anions and other molecules interacting with zinc proteins, such as sulfamide, sulfamic acid, phenylboronic/arsonic acids. TcCA was inhibited in the low micromolar range by iodide, cyanate, thiocyanate, hydrogensulfide and trithiocarbonate (KIs in the range of 44-93 μM), but the best inhibitor was diethyldithiocarbamate (KI=5 μM). Sulfamide showed an inhibition constant of 120 μM, but sulfamic acid was much less effective (KI of 10.6 mM). The discovery of diethyldithiocarbamate as a low micromolar TcCA inhibitor may be useful to detect leads for developing anti-Trypanosoma agents with a diverse mechanism of action compared to clinically used drugs (benznidazole, nifurtimox) for which significant resistance emerged.
原生动物病原体克氏锥虫，恰加斯病的病原体，编码一种α-类碳酸酐酶（CA，EC 4.2.1.1），TcCA，最近的研究表明它对其生命周期至关重要。巯基化合物是一类强效的 TcCA 抑制剂，也被证明可以在体外阻止病原体的生长。在这里，我们报告了无机和络合阴离子以及与锌蛋白相互作用的其他分子（如磺胺、氨基磺酸、苯硼酸/砷酸）对 TcCA 的抑制作用。碘化物、氰酸盐、硫氰酸盐、硫化氢和三硫代碳酸酯（KI 值在 44-93 μM 范围内）以低微摩尔范围抑制 TcCA，但最佳抑制剂是二乙基二硫代氨基甲酸盐（KI=5 μM）。磺胺表现出 120 μM 的抑制常数，但氨基磺酸的效果要差得多（KI 为 10.6 mM）。发现二乙基二硫代氨基甲酸盐是一种低微摩尔 TcCA 抑制剂，可能有助于发现具有与临床使用药物（苯并咪唑、硝呋替莫）不同作用机制的抗锥虫药物先导物，因为这些药物已经出现了明显的耐药性。
