CYP51 as drug targets for fungi and protozoan parasites: past, present and future.
CYP51 as drug targets for fungi and protozoan parasites: past, present and future.
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DOI：
10.1017/s0031182018000562
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发表时间：
2018-12
期刊：
影响因子：
2.4
通讯作者：
Waterman MR
中科院分区：
文献类型：
--
作者：
Lepesheva GI;Friggeri L;Waterman MR
真菌和原生动物等单细胞真核病原体对人类感染的治疗效率仍然很不令人满意。例如，危重患者、免疫抑制患者或癌症后患者医院内真菌血症的死亡率通常超过50%。一组六种全身性临床唑类药物(甾醇14α去甲基酶(CyP51)抑制剂)代表了一线抗真菌治疗。所有这些药物都是通过监测它们对真菌细胞生长的影响而被经验发现的，尽管已经被证明它们通过在14α阶段阻止真菌中麦角固醇的生物合成来杀死真菌细胞-固醇核的去甲基化。本文简要介绍了唑类抗真菌药物的发展历史，概述了目前临床上使用的唑类药物的情况，描述了将其用于治疗人类感染原虫寄生虫的尝试，这些原虫与真菌相似，也产生内源性甾醇，并讨论了最近获得的关于CYP51结构/功能和抑制作用的知识。我们相信，这些信息将有助于从传统的表型筛选转向实际的靶向药物发现范式，这将使新的、更有效的、以病原体为导向的CYP51抑制剂的开发合理化并大大加速。
The efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post cancer patients often exceed 50%. A set of six systemic clinical azoles (sterol 14α-demethylase (CYP51) inhibitors) represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking biosynthesis of ergosterol in fungi at the stage of 14α-demethylation of the sterol nucleus. This review briefs the history of antifungal azoles, outlines the situation with the current clinical azole-based drugs, describes the attempts of their repurposing for treatment of human infections with the protozoan parasites that, similar to fungi, also produce endogenous sterols, and discusses the most recently acquired knowledge on the CYP51 structure/function and inhibition. It is our belief that this information should be helpful in shifting from the traditional phenotypic screening to the actual target-driven drug discovery paradigm, which will rationalize and substantially accelerate the development of new, more efficient and pathogen-oriented CYP51 inhibitors.