title: Anion inhibition studies of the α-carbonic anhydrase from the protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease.
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.
authors.affiliation: Institute of Biomedical Technology, Fimlab Ltd, School of Medicine and BioMediTech, University of Tampere and Tampere University Hospital, Medisiinarinkatu 3, 33520 Tampere, Finland.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Pan
authors.forename: Alane Beatriz
authors.initials: AB
authors.lastname: Vermelho
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000838:Anions / Q000737:chemistry / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D004050:Ditiocarb / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D000838:Anions; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D004050:Ditiocarb