Relaxed Substrate Requirements of Sterol 14α-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition,Journal of Medicinal Chemistry

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Relaxed Substrate Requirements of Sterol 14α-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-29 , DOI: 10.1021/acs.jmedchem.1c01710
Tatiana Y Hargrove ₁ , Zdzislaw Wawrzak ₂ , Girish Rachakonda ₃ , W David Nes ₄ , Fernando Villalta ₃ , F Peter Guengerich ₁ , Galina I Lepesheva _{1,

5}

Affiliation

Naegleria fowleri is the protozoan pathogen that causes primary amoebic meningoencephalitis (PAM), with the death rate exceeding 97%. The amoeba makes sterols and can be targeted by sterol biosynthesis inhibitors. Here, we characterized N. fowleri sterol 14-demethylase, including catalytic properties and inhibition by clinical antifungal drugs and experimental substituted azoles with favorable pharmacokinetics and low toxicity. None of them inhibited the enzyme stoichiometrically. The highest potencies were displayed by posaconazole (IC₅₀ = 0.69 μM) and two of our compounds (IC₅₀ = 1.3 and 0.35 μM). Because both these compounds penetrate the brain with concentrations reaching minimal inhibitory concentration (MIC) values in an N. fowleri cellular assay, we report them as potential drug candidates for PAM. The 2.1 Å crystal structure, in complex with the strongest inhibitor, provides an explanation connecting the enzyme weaker substrate specificity with lower sensitivity to inhibition. It also provides insight into the enzyme/ligand molecular recognition process and suggests directions for the design of more potent inhibitors.

中文翻译：

福氏耐格里阿米巴甾醇 14α-脱甲基酶的底物要求放宽并伴随着抑制抗性

福氏耐格里阿米巴是引起原发性阿米巴脑膜脑炎（PAM）的原虫病原体，死亡率超过97%。阿米巴原虫产生甾醇，并且可以成为甾醇生物合成抑制剂的目标。在这里，我们对福氏奈瑟菌甾醇14-去甲基酶进行了表征，包括临床抗真菌药物和实验取代唑类药物的催化特性和抑制作用，具有良好的药代动力学和低毒性。它们都没有以化学计量抑制酶。_{泊沙康唑 (IC 50} = 0.69 μM) 和我们的两种化合物（IC ₅₀ = 1.3 和 0.35 μM）显示出最高的效力。因为这两种化合物都能渗透到大脑，其浓度达到最低抑制浓度 (MIC) 值N. fowleri细胞测定，我们将它们报告为 PAM 的潜在候选药物。2.1 Å 晶体结构与最强的抑制剂复合，解释了酶较弱的底物特异性与较低的抑制敏感性之间的联系。它还提供了对酶/配体分子识别过程的深入了解，并为设计更有效的抑制剂提供了方向。

更新日期：2021-12-09

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