Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α‑Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease

• Published in: Journal of medicinal chemistry Vol. 56; no. 4; pp. 1761 - 1771
• Main Authors: Pan, Peiwen, Vermelho, Alane Beatriz, Capaci Rodrigues, Giseli, Scozzafava, Andrea, Tolvanen, Martti E. E, Parkkila, Seppo, Capasso, Clemente, Supuran, Claudiu T
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.02.2013
• Subjects: Amino Acid Sequence; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - genetics; Chagas Disease - parasitology; Cloning, Molecular; Humans; Molecular Sequence Data; Phylogeny; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Protozoan Proteins - genetics; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4000616

An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K I values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K I values in the range 61.6–93.6 nM. The thiols were the most potent in vitro inhibitors (K I values of 21.1–79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.