Discovery of Monoterpenoid Indole Alkaloids Targeting CCN1 to Suppress Autophagy for the Treatment of Hypoxic Kidney Injury
Xue Qiao, Shun-Qing Chen, Ariel M. Sarotti, Jixian Zhang, Yu-Ting Zhong, Wei-Chen Chen, Xiaofen Wang, Wumei Wang, Jianying Huang, Xiao-Yan Wu, Hui-Ming Wang, Shugeng Cao, Zhengqiu Li, Qihao Wu, Yuling Xiao, Xuechuan Hong, You-Sheng CaiAbstract
Hypoxic kidney injury remains difficult to treat due to the lack of therapies that effectively prevent podocyte injury and disease progression. Bioassay-guided investigation of Tabernaemontana pandacaqui yielded ten monoterpenoid indole alkaloids (MIAs), including eight new compounds with five unprecedented carbon skeletons. Notably, compound 6 is the first MIA monomer with a 6/5/6/5/6 pentacyclic diazaspiro[acenaphthylene-3,2′-indoline]-dione core containing three nitrogen atoms. Cytoprotective screening identified 2 and 6 with nanomolar potency (EC50 ≈ 22 nM). In a chronic hypoxic kidney injury mouse model, both compounds alleviated renal injury by restoring podocyte integrity and normalizing HIF-1α, p62, and LC3-II. Integrated activity-based protein profiling, chemical proteomics, RNA sequencing, molecular docking, and functional validation identified cellular communication network factor 1 (CCN1) as the molecular target of 2. Together, these findings expand the chemical space of MIAs, establish CCN1 as a therapeutic target for hypoxic kidney injury, and identify MIAs as a promising class of renoprotective leads.