摘要
近期对开发新抗菌剂的可行性引起了更多兴趣。当今临床使用的主要类型抗生素主要针对以下四种传统靶点:a) 细胞壁生物合成;b)蛋白质生物合成;c)DNA和RNA生物合成;d)叶酸生物合成。近期,自从碳酸酐酶(CAs, EC 4.2.1.1)在许多细菌中被得到证明,开始具体研究其致病菌,搜索抗生素的新的作用机制, CAS对生命循环必不可少,并且它们的抑制会导致病原体的生长损伤或缺陷。Case催化一种简单但是生理学相关的反应, 二氧化碳水化为碳酸盐和氢。迄今为止多种CA抑制剂(CAIs)被熟知:金属配位反应和未取代的磺胺类药物,其通过取代非蛋白锌配位体或添加至金属的配位层,与酶的Zn(II) 离子螯合,产生的三角双锥物质是传统的最常被研究的化合物。多数情况下检测的有效抑制剂,他们中的一些也会抑制体内细菌生长。然而,检测的极少抑制剂也会对人体的细菌有选择性,脱靶的亚型如hCA II。采用基于结构的药物设计步骤,我们估计它将会有可能优先地抑制细菌而达到希望的选择性,而非CA亚型宿主。
关键词: 阳离子,抗菌剂,抗感染药,碳酸酐酶,CA抑制剂,水合酶活性,病原体,选择性抑制剂,磺胺类药,X射线
Current Medicinal Chemistry
Title:An Overview of the Selectivity and Efficiency of the Bacterial Carbonic Anhydrase Inhibitors
Volume: 22 Issue: 18
Author(s): C. Capasso and C.T. Supuran
Affiliation:
关键词: 阳离子,抗菌剂,抗感染药,碳酸酐酶,CA抑制剂,水合酶活性,病原体,选择性抑制剂,磺胺类药,X射线
摘要: The possibility to develop new antibacterial agents raised much interest recently. The main classes of antibiotics clinically used nowadays act towards the inhibition of four classical targets: a) cell wall biosynthesis; b) protein biosynthesis; c) DNA and RNA biosynthesis; d) folate biosynthesis. Recently, carbonic anhydrases (CAs, EC 4.2.1.1) started to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria, CAs are essential for the life cycle of the organism and that their inhibition leads to growth impairment or growth defects of the pathogen. CAs catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. Several classes of CA inhibitors (CAIs) are known to date: the metal complexing anions and the unsubstituted sulfonamides, which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere, generating trigonal– bipyramidal species are the classical, most frequently investigated ones. In many cases effective inhibitors were detected, some of which also inhibited the bacterial growth in vivo. However, very few of the detected inhibitors were also selective for the bacterial over the human, off target isoforms such as hCA II. Using structure-based drug design processes, we estimate that it will be possible to achieve the desired selectivity for inhibiting preferentially the bacterial but not the host CA isoforms.
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Cite this article as:
C. Capasso and C.T. Supuran , An Overview of the Selectivity and Efficiency of the Bacterial Carbonic Anhydrase Inhibitors, Current Medicinal Chemistry 2015; 22 (18) . https://dx.doi.org/10.2174/0929867321666141012174921
DOI https://dx.doi.org/10.2174/0929867321666141012174921 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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