结核分枝杆菌 CYP450 酶作为潜在药物靶标的研究进展  

Research progresses of Mycobacterium tuberculosis cytochrome P450s as a potential drug target

作　　者：卢芸[1] 乔峰[1] 游雪甫[1] 杨信怡[1] 

机构地区：[1]中国医学科学院、北京协和医学院医药生物技术研究所,北京100050

出　　处：《药学学报》2014年第4期427-434,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81273427);国家“重大新药创制”科技重大专项(2012ZX09301002-001,2012ZX09301002-005)

摘　　要：新型抗结核药物靶标的寻找与验证是抗结核新药发现的关键环节。近期研究发现,结核分枝杆菌编码表达20余种细胞色素P450酶(CYP450s)。这些CYP450s在活跃或潜伏期结核分枝杆菌(Mtb)的脂质代谢与合成、胆固醇利用、呼吸链电子传递等方面扮演十分重要的角色。目前6个亚型的蛋白质晶体结构已被阐明,提示其具有成为抗结核药物靶标的潜力。本文将结合最新发表的文献,主要从Mtb CYP450酶系同源性、各亚型结构与功能、与唑类等小分子抑制剂相互作用机制等角度,总结该类蛋白可靶性的依据,为进一步的抗结核药物筛选与设计提供参考。Identification and validation of a new target is one of the most important steps for new antituberculosis （TB） drug discovery. Researches have shown that Mycobacterium tuberculosis （Mtb） encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets. In this paper, the phylogenetic analysis, the structural features, and the enzymatic functions of Mtb CYPs, as well as the mechanism of interactions with selective inhibitors such as azole antifungal agents for the CYPs have been reviewed and summarized. The druggability of the CYPs has also been analyzed for their further utility as targets in high throughput screening and rational design of more selective inhibitors.

关 键 词：结核分枝杆菌 CYP450 药物靶标 

分 类 号：R963[医药卫生—微生物与生化药学]