2. Academic Validation
  3. Indole selectively suppresses aldosterone overproduction via binding to the catalytic site of CYP11B2

Indole selectively suppresses aldosterone overproduction via binding to the catalytic site of CYP11B2

  • Biochem Pharmacol. 2025 Jul 26;242(Pt 1):117190. doi: 10.1016/j.bcp.2025.117190.
Wuchao Li 1,  Jinbo Hu 2,  Yifan He 1,  Chuan Peng 3,  Junlong Li 2,  Yong Xu 4,  Wei Huang 4,  Qifu Li 5,  Linqiang Ma 6,  Shumin Yang 7
Affiliations

Affiliations

  • 1 Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
  • 5 Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: liqifu@yeah.net.
  • 6 Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: tom_linqiang@163.com.
  • 7 Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: ysm@hospital.cqmu.edu.cn.
PMID: 40721010 DOI: 10.1016/j.bcp.2025.117190
Abstract

Hyperaldosteronism, characterized by aldosterone overproduction, increases the risk of renal damage and cardiovascular events. Aldosterone synthase (CYP11B2), the rate-limiting enzyme in aldosterone biosynthesis, has emerged as a promising therapeutic target, but developing selective CYP11B2 inhibitors remains challenging due to its high structural similarity to 11β-hydroxylase (CYP11B1). Indole, a natural heterocyclic compound derived from Plants and bacteria, has therapeutic and regulatory effects in inflammation and Endocrinology. A series of chemically synthesized indole derivatives have been reported to modulate CYP11B2. However, the regulatory role of indole, the naturally occurring parent compound, in aldosterone synthesis remains unclear. In this study, we evaluated the selective inhibitory effects and mechanisms of indole on aldosterone overproduction using both in vitro and in vivo models. Indole significantly suppressed aldosterone synthesis both in a NaCl-depleted diet-induced mouse model of hyperaldosteronism and in NCI-H295R cells pre-stimulated for aldosterone production, without markedly affecting corticosterone synthesis in mice or cortisol synthesis in cells-both primarily catalyzed by CYP11B1. Further assays in transfected HEK-293T cells confirmed that indole selectively inhibited CYP11B2 catalytic activity. Molecular docking, molecular dynamics simulations, and bio-layer interferometry identified Phe130 as the critical residue mediating the interaction between indole and CYP11B2. These findings reveal that indole can selectively inhibit aldosterone overproduction by targeting Phe130 of CYP11B2, highlighting its potential as a novel therapeutic candidate for hyperaldosteronism.

Keywords

Aldosterone synthase; Hyperaldosteronism; Indole; Selective enzyme inhibitor.

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