Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect

Ding, Li1,2; Nan, Wen-Hao1,2; Zhu, Xian-Bing1,2,3; Li, Xiao-Ming1,2; Zhou, Li-Yan4; Chen, Hou-Jie2,5; Yu, Lu2,5; Khan, Fahim Ullah1,2; Zhong, Han-Bing6; Shi, Xiao-Jun1,2

2019-04

10.1111/cns.13062

CNS Neuroscience & Therapeutics   影响因子和分区

1755-5930

1755-5949

Autophagy is an essential cellular process concern with cellular homeostasis down-regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34(cdc2)/cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (Delta psi m) and could rescue dopaminergic neurons in MPTP-treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.

autophagy FK506 low immunosuppression mitochondria protection neurodegenerative diseases rapamycin

SCI

英语

通讯

Shenzhen Science and Technology Program[JCYJ20170412153453623] ; Shenzhen Science and Technology Program[JCYJ20130402145002433]

Neurosciences & Neurology ; Pharmacology & Pharmacy

Neurosciences ; Pharmacology & Pharmacy

WOS:000461901900005

WILEY

Web of Science

1.Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China
2.Tsinghua Univ, Grad Sch Shenzhen, Shenzhen, Peoples R China
3.McGill Univ, Dept Biochem, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ, Canada
4.Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Lab Chem Genom, Shenzhen, Peoples R China
5.Shenzhen Modobiotec CO, Shenzhen, Peoples R China
6.South Univ Sci & Technol, Dept Biol, Shenzhen, Guangdong, Peoples R China

Ding, Li,Nan, Wen-Hao,Zhu, Xian-Bing,et al. Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect[J]. CNS Neuroscience & Therapeutics,2019,25(4):452-464.

Ding, Li.,Nan, Wen-Hao.,Zhu, Xian-Bing.,Li, Xiao-Ming.,Zhou, Li-Yan.,...&Shi, Xiao-Jun.(2019).Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect.CNS Neuroscience & Therapeutics,25(4),452-464.

Ding, Li,et al."Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect".CNS Neuroscience & Therapeutics 25.4(2019):452-464.