Hyperaldosteronism is a common disease that is closely related to endocrine hypertension and other cardiovascular diseases. Cytochrome P450 11B2 (CYP11B2), an important enzyme in aldosterone (ALD) synthesis, is a promising target for the treatment of hyperaldosteronism. However, selective inhibitors targeting CYP11B2 are still lacking due to the high similarity with CYP11B1. In this study, atractylenolide-I (AT-I) was found to significantly reduce the production of ALD but had no effect on cortisol synthesis, which is catalyzed by CYP11B1. Chemical biology studies revealed that due to the presence of Ala320, AT-I is selectively bound to the catalytic pocket of CYP11B2, and the C8/C9 double bond of AT-I can be epoxidized, which then undergoes nucleophilic addition with the sulfhydryl group of Cys450 in CYP11B2. The covalent binding of AT-I disrupts the interaction between heme and CYP11B2 and inactivates CYP11B2, leading to the suppression of ALD synthesis; AT-I shows a significant therapeutic effect for improving hyperaldosteronism.

醛固酮增多症是一种与内分泌性高血压等心血管疾病密切相关的常见病。细胞色素 P450 11B2 (CYP11B2) 是醛固酮 (ALD) 合成中的重要酶，是治疗醛固酮增多症的有希望的靶点。然而，由于与 CYP11B1 的高度相似性，仍然缺乏针对 CYP11B2 的选择性抑制剂。在这项研究中，发现白术内酯-I (AT-I) 可显着减少 ALD 的产生，但对由 CYP11B1 催化的皮质醇合成没有影响。化学生物学研究表明，由于 Ala320 的存在，AT-I 选择性结合到 CYP11B2 的催化口袋上，AT-I 的 C8/C9 双键可以被环氧化，然后与巯基发生亲核加成反应。 CYP11B2 中的 Cys450。AT-I 的共价结合破坏了血红素与 CYP11B2 之间的相互作用并使 CYP11B2 失活，导致 ALD 合成受到抑制；AT-I显示出改善醛固酮增多症的显着治疗效果。