Anion inhibition studies of the ¦Á-carbonic anhydrase from the protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease

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• 作者：Peiwen Pan ; Alane Beatriz Vermelho ; Andrea Scozzafava ; Seppo Parkkila ; Clemente Capasso ; Claudiu T. Supuran
• 关键词：Carbonic anhydrase ; Anion ; Alpha-class enzyme ; Inhibitor ; Trypanosoma cruzi
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 August, 2013
• 年：2013
• 卷：21
• 期：15
• 页码：4472-4476
• 全文大小：561 K

文摘

The protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease, encodes an ¦Á-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 (K_Is in the range of 44-93 ¦ÌM), but the best inhibitor was diethyldithiocarbamate (K_I = 5 ¦ÌM). Sulfamide showed an inhibition constant of 120 ¦ÌM, but sulfamic acid was much less effective (K_I 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.