Novel Prenylated Indole Alkaloids with Neuroprotection on SH-SY5Y Cells against Oxidative Stress Targeting Keap1-Nrf2

• Published in: Marine drugs 2022-03, Vol.20 (3), p.191
• Main Authors: Xiao, Xueyang, Tong, Zhou, Zhang, Yuexing, Zhou, Hui, Luo, Mengying, Hu, Tianhui, Hu, Ping, Kong, Luqi, Liu, Zeqin, Yu, Chan, Huang, Zhiyong, Hu, Linzhen
• Format: Article
• Language: English
• Subjects: Aetiology; Alkaloids; Aspergillus ochraceus - chemistry; Aspergillus ochraceus - metabolism; Body condition; Carbon; Cell Line, Tumor; Cells; Cytoplasm; Etiology; Fungi; Gene expression; Glutathione; Glutathione - metabolism; Humans; Hydrophobicity; Indole Alkaloids - chemistry; Indole Alkaloids - metabolism; Indole Alkaloids - pharmacology; Indoles; Keap1–Nrf2; Kelch-Like ECH-Associated Protein 1 - metabolism; Molecular docking; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Movement disorders; Neurodegenerative diseases; Neuroprotection; Neuroprotection - drug effects; Neuroprotective Agents - chemistry; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; NMR; Nuclear magnetic resonance; Oxidative stress; Oxidative Stress - drug effects; Parkinson's disease; Penicillium - chemistry; Penicillium - metabolism; prenylated indole alkaloids; Prenylation; Proteins; Reactive oxygen species; Spectrum analysis; Translocation
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md20030191

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). Molecules non-covalently binding to the Keap1-Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine ( ), and asperpendoline ( ) with a scarce skeleton of pyrimido[1,6- ]indole were discovered from the co-cultivated fungi of MCCC 3A00521 and sp. HUBU 0120. Compound exhibited potential neuroprotective activity on SH-SY5Y cells against oxidative stress. Molecular mechanism research demonstrated that inhibited Keap1 expression, resulting in the translocation of Nrf2 from the cytoplasm to the nucleus, activating the downstream genes expression of HO-1 and NQO1, leading to the reduction in reactive oxygen species (ROS) and the augment of glutathione. Molecular docking and dynamic simulation analyses manifested that interacted with Keap1 (PDB ID: 1X2R) via forming typical hydrogen and hydrophobic bonds with residues and presented less fluctuation of RMSD and RMSF during a natural physiological condition.