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首页> 外文期刊>Journal of Medicinal Chemistry >Validation of Human Sterol 14 alpha-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors
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Validation of Human Sterol 14 alpha-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors

机译：人甾醇14α-脱甲基酶（CYP51）可耐药性：结构引导的设计，合成和化学计量，功能性不可逆抑制剂的评价

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摘要

Sterol 14 alpha-demethylases (CYP51) are the cytochrome P450 enzymes required for biosynthesis of sterols in eukaryotes, the major targets for antifungal agents and prospective targets for treatment of protozoan infections. Human CYP51 could be and, for a while, was considered as a potential target for cholesterol-lowering drugs (the role that is now played by statins, which are also in clinical trials for cancer) but revealed high intrinsic resistance to inhibition. While microbial CYP51 enzymes are often inhibited stoichiometrically and functionally irreversibly, no strong inhibitors have been identified for human CYP51. In this study, we used comparative structure/functional analysis of CYP51 orthologs from different biological kingdoms and employed site-directed mutagenesis to elucidate the molecular basis for the resistance of the human enzyme to inhibition and also designed, synthesized, and characterized new compounds. Two of them inhibit human CYP51 functionally irreversibly with their potency approaching the potencies of azole drugs currently used to inhibit microbial CYP51.
机译：甾醇14α-脱甲基酶（CYP51）是真核生物中生物合成所需的细胞色素P450酶，抗真菌剂的主要靶标和治疗原生动物感染的前瞻性靶标。人类CYP51可以是，暂时被认为是胆固醇降低药物的潜在靶标（他汀类药物的作用，也在癌症的临床试验中，但揭示了对抑制的高度抗性。虽然通常抑制微生物CYP51酶，但在功能上不可逆地抑制，但没有针对人CYP51鉴定出强抑制剂。在本研究中，我们使用了来自不同生物王国的CYP51 Orthologs的比较结构/功能分析，并使用现场定向的诱变来阐明人酶抗抑制作用和设计，合成和表征新化合物的分子基础。其中两者抑制了人类CYP51，功能性不可逆转，其效力接近目前用于抑制微生物CYP51的唑类药物的疗效。

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