中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5(H88Y) Mutant Mice

文献类型：期刊论文

作者Yun, Ying1,2; Zhang, Chenlu3; Guo, Shimeng4; Liang, Xiaoying1; Lan, Yuan4; Wang, Min1; Zhuo, Ning2,3; Yin, Jianpeng5; Liu, Huanan3; Gu, Min3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-08-26
卷号64期号:16页码:12181-12199
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c00851
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn)
英文摘要Takeda G protein-coupled receptor 5 (TGR5) is a promising target for treating metabolic syndrome and inflammatory diseases. Herein, we identified a new series of betulinic acid derivatives as potent TGR5 agonists, which show remarkable activity on human (h) and canine (c) TGR5 but exhibit unpromising activity on murine (m) TGR5. Species difference was also observed with many other reported TGR5 agonists. Therefore, we screened 29 amino acids which were conserved in hTGR5 and cTGR5 but different in mTGR5 and found a key amino acid, H88 in mTGR5 (Y89 in hTGR5), which contributed to the species difference. With the CRISPR/Cas9 system, the mTGR5(H88Y) mutation was introduced into mice, and the optimized compound 11d-Na displayed a significant glucose-lowering effect and stimulated GLP-1 and insulin secretion in TGR5(H88Y) mice but not in wild-type animals. Taken together, our study provides a useful tool to bridge the gap of species difference and discovers a potent TGR5 agonist for further investigation.
WOS关键词PEPTIDE-1 SECRETION ; BILE-ACIDS ; RECEPTOR ; GPBAR1 ; ACTIVATION ; GLUCOSE
资助项目National Natural Science Foundation of China (NNSFC)[82030109] ; National Natural Science Foundation of China (NNSFC)[81730099] ; National Natural Science Foundation of China (NNSFC)[82003572] ; Shanghai Commission of Science and Technology[19140903900] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040332] ; Shandong Provincial Natural Science Foundation, China[ZR2019PB025]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000692012400023
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/297810]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Nan, Fajun
作者单位1.Chinese Acad Sci, CAS Key Lab Receptor Res, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
5.Yantai Inst Mat Med, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Shandong, Peoples R China
6.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Yun, Ying,Zhang, Chenlu,Guo, Shimeng,et al. Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5(H88Y) Mutant Mice[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(16):12181-12199.
APA Yun, Ying.,Zhang, Chenlu.,Guo, Shimeng.,Liang, Xiaoying.,Lan, Yuan.,...&Nan, Fajun.(2021).Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5(H88Y) Mutant Mice.JOURNAL OF MEDICINAL CHEMISTRY,64(16),12181-12199.
MLA Yun, Ying,et al."Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5(H88Y) Mutant Mice".JOURNAL OF MEDICINAL CHEMISTRY 64.16(2021):12181-12199.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。