Del Prete Sonia, Vullo Daniela, De Luca Viviana, Carginale Vincenzo, Ferraroni Marta, Osman Sameh M, AlOthman Zeid, Supuran Claudiu T, Capasso Clemente
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 81, Napoli, Italy; Università degli Studi di Firenze, Dipartimento Di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
Università degli Studi di Firenze, Dipartimento Di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
Bioorg Med Chem. 2016 Mar 1;24(5):1115-20. doi: 10.1016/j.bmc.2016.01.037. Epub 2016 Jan 22.
The genome of the pathogenic bacterium Vibrio cholerae encodes for three carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β- and γ-classes. VchCA, the α-CA from this species was investigated earlier, whereas the β-class enzyme, VchCAβ was recently cloned, characterized kinetically and its X-ray crystal structure reported by this group. Here we report an inhibition study with sulfonamides and one sulfamate of this enzyme. The best VchCAβ inhibitors were deacetylated acetazolamide and methazolamide and hydrochlorothiazide, which showed inhibition constants of 68.2-87.0nM. Other compounds, with medium potency against VchCAβ, (KIs in the range of 275-463nM), were sulfanilamide, metanilamide, sulthiame and saccharin whereas the clinically used agents such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, zonisamide and celecoxib were micromolar inhibitors (KIs in the range of 4.51-8.57μM). Identification of potent and possibly selective inhibitors of VchCA and VchCAβ over the human CA isoforms, may lead to pharmacological tools useful for understanding the physiological role(s) of this under-investigated enzymes.
致病性细菌霍乱弧菌的基因组编码三种碳酸酐酶（CAs，EC 4.2.1.1），分别属于α、β和γ类。该物种的α-CA即VchCA，此前已被研究，而β类酶VchCAβ最近被克隆、进行了动力学表征，并且该团队报道了其X射线晶体结构。在此，我们报道了对该酶的磺胺类药物和一种氨基磺酸盐的抑制研究。最佳的VchCAβ抑制剂是脱乙酰乙酰唑胺、甲醋唑胺和氢氯噻嗪，其抑制常数为68.2 - 87.0 nM。其他对VchCAβ具有中等抑制效力（抑制常数在275 - 463 nM范围内）的化合物有磺胺、间胺黄、舒噻美和糖精，而临床使用的药物如乙酰唑胺、甲醋唑胺、乙氧唑胺、多佐胺、唑尼沙胺和塞来昔布是微摩尔级抑制剂（抑制常数在4.51 - 8.57μM范围内）。鉴定出比人类CA同工型更有效且可能具有选择性的VchCA和VchCAβ抑制剂，可能会产生有助于理解这种研究不足的酶的生理作用的药理学工具。
