Institute of Biomedical Technology and BioMediTech, University of Tampere , 33520 Tampere, Finland.
J Med Chem. 2013 Sep 26;56(18):7372-81. doi: 10.1021/jm400939k. Epub 2013 Sep 13.
Leishmaniasis is an infection provoked by protozoans belonging to the genus Leishmania. Among the many species and subsepecies of such protozoa, Leishmania donovani chagasi causes visceral leishmaniasis. A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism, denominated here LdcCA. LdcCA possesses effective catalytic activity for the CO2 hydration reaction, with kcat of 9.35 × 10(5) s(-1) and kcat/KM of 5.9 × 10(7) M(-1) s(-1). A large number of aromatic/heterocyclic sulfonamides and 5-mercapto-1,3,4-thiadiazoles were investigated as LdcCA inhibitors. The sulfonamides were medium potency to weak inhibitors (KI values of 50.2 nM-9.25 μM), whereas some heterocyclic thiols inhibited the enzyme with KIs in the range of 13.4-152 nM. Some of the investigated thiols efficiently inhibited the in vivo growth of Leishmania chagasi and Leishmania amazonensis promastigotes, by impairing the flagellar pocket and movement of the parasites and causing their death. The β-CA from Leishmania spp. is proposed here as a new antileishmanial drug target.
利什曼病是一种由原生动物属利什曼原虫引起的感染。在这些原生动物的许多种和亚种中，恰加斯利什曼原虫引起内脏利什曼病。从这种生物体中克隆并表征了一种β-碳酸酐酶（CA，EC 4.2.1.1），在这里称为 LdcCA。LdcCA 对 CO2 水合反应具有有效的催化活性，kcat 为 9.35×10(5)s(-1)，kcat/KM 为 5.9×10(7)M(-1)s(-1)。大量的芳族/杂环磺酰胺和 5-巯基-1,3,4-噻二唑被用作 LdcCA 的抑制剂。磺酰胺是中等强度到弱抑制剂（KI 值为 50.2 nM-9.25 μM），而一些杂环硫醇则以 13.4-152 nM 的 KI 范围抑制该酶。一些研究的硫醇有效地抑制了利什曼原虫和利什曼原虫前鞭毛体的体内生长，通过损害鞭毛囊和寄生虫的运动并导致其死亡。利什曼属的β-CA 在这里被提议作为一种新的抗利什曼药物靶点。
