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

详细信息    查看全文

• 作者：Peiwen Pan ; Alane Beatriz Vermelho ; Giseli Capaci Rodrigues ; Andrea Scozzafava ; Martti E. E. Tolvanen ; Seppo Parkkila ; Clemente Capasso ; Claudiu T. Supuran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1761-1771
• 全文大小：472K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

An 伪-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 渭M), whereas some heterocyclic compounds inhibited the enzyme with K_I values in the range 61.6鈥?3.6 nM. The thiols were the most potent in vitro inhibitors (K_I values of 21.1鈥?9.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.