期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 21, 期 15, 页码 4472-4476出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.05.058
关键词
Carbonic anhydrase; Anion; Alpha-class enzyme; Inhibitor; Trypanosoma cruzi
资金
- FP7 EU project (Metoxia)
- Academy of Finland
- Sigrid Juselius Foundation
- Competitive Research Funding of Tampere University Hospital [9N054]
- Coordenacao de Aperfeicoamento Pessoal de Nivel Superior (CAPES)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (MCT/CNPq)
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
The protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease, encodes an alpha-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(I)s in the range of 44-93 mu M), but the best inhibitor was diethyldithiocarbamate (K-I = 5 mu M). Sulfamide showed an inhibition constant of 120 mu M, 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. (C) 2013 Elsevier Ltd. All rights reserved.
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