Anion inhibition studies of the α-carbonic anhydrase from the protozoan pathogen Trypanosoma cruzi,the causative agent of Chagas disease |
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| Authors: | Peiwen Pan Alane Beatriz Vermelho Andrea Scozzafava Seppo Parkkila Clemente Capasso Claudiu T Supuran |
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| Institution: | 1. Institute of Biomedical Technology, Fimlab Ltd, School of Medicine and BioMediTech, University of Tampere and Tampere University Hospital, Medisiinarinkatu 3, 33520 Tampere, Finland;2. Laboratório Proteases de Microrganismos, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro – UFRJ, CCS Bloco I, Sala 32, Cidade Universitária, Av. Carlos Chagas Filho, 373, Ilha do Fundão, Rio de Janeiro R.J., Brazil;3. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy;4. Istituto di Biochimica delle Proteine – CNR, Via P. Castellino 111, 80131 Napoli, Italy;5. Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy |
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| Abstract: | 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. |
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| Keywords: | Carbonic anhydrase Anion Alpha-class enzyme Inhibitor |
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