Identification and structural insight of an effective PPAR gamma modulator with improved therapeutic index for anti-diabetic drug discovery
文献类型：期刊论文
| 作者 | Jiang, Haowen1,2,4; Zhou, X. Edward5; Shi, Jingjing3 ; Zhou, Zhi1,2; Zhao, Guanguan3; Zhang, Xinwen4; Sun, Yili4; Suino-Powell, Kelly5; Ma, Lei1,2; Gao, Hui1,2
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| 刊名 | CHEMICAL SCIENCE
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| 出版日期 | 2020-02-28 |
| 卷号 | 11期号:8页码:2260-2268 |
| ISSN号 | 2041-6520 |
| DOI | 10.1039/c9sc05487a |
| 通讯作者 | Li, Jia(jli@simm.ac.cn) ; Li, Jingya(jyli@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Yi, Wei(yiwei@gzhmu.edu.cn) |
| 英文摘要 | Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPAR gamma-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPAR gamma modulator (SPPAR gamma M), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPAR gamma ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPAR gamma Ms as safe and highly efficacious anti-diabetic drugs. |
| WOS关键词 | ACTIVATED-RECEPTOR-GAMMA ; FATTY-ACID ; IN-VITRO ; AGONISTS ; LIGAND ; THIAZOLIDINEDIONES ; BINDING ; ROSIGLITAZONE ; DERIVATIVES ; DESIGN |
| 资助项目 | Jay and Betty Van Andel Foundation ; Youth Innovation Promotion Association CAS ; K. C. Wong Education Foundation ; Strategic Pilot Program of the Chinese Academy of Sciences[XDA12040204] ; National Natural Science Foundation of China[81330007] ; National Natural Science Foundation of China[U1601227] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81502909] ; National Natural Science Foundation of China[21877020] ; Shanghai Commission of Science and Technology[16JC1405000] ; Guangdong Natural Science Funds for Distinguished Young Scholar[2017A030306031] ; Science and Technology Programs of Guangdong Province[2015B020225006] ; Natural Science Foundation Research Team of Guangdong Province[2018B030312001] ; Amway (China) |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| 出版者 | ROYAL SOC CHEMISTRY |
| WOS记录号 | WOS:000518011700024 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/281548]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Jia; Li, Jingya; Xu, H. Eric; Yi, Wei |
| 作者单位 | 1.Guangzhou Med Univ, Guangzhou Municipal & Guangdong Prov Key Lab Prot, State Key Lab Resp Dis, Sch Pharmaceut Sci, Guangzhou 511436, Guangdong, Peoples R China 2.Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China 3.Chinese Acad Sci, VARI SIMM Ctr, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Van Andel Res Inst, Ctr Canc & Cell Biol, Struct Biol Program, Grand Rapids, MI 49503 USA |
| 推荐引用方式 GB/T 7714 | Jiang, Haowen,Zhou, X. Edward,Shi, Jingjing,et al. Identification and structural insight of an effective PPAR gamma modulator with improved therapeutic index for anti-diabetic drug discovery[J]. CHEMICAL SCIENCE,2020,11(8):2260-2268. |
| APA | Jiang, Haowen.,Zhou, X. Edward.,Shi, Jingjing.,Zhou, Zhi.,Zhao, Guanguan.,...&Yi, Wei.(2020).Identification and structural insight of an effective PPAR gamma modulator with improved therapeutic index for anti-diabetic drug discovery.CHEMICAL SCIENCE,11(8),2260-2268. |
| MLA | Jiang, Haowen,et al."Identification and structural insight of an effective PPAR gamma modulator with improved therapeutic index for anti-diabetic drug discovery".CHEMICAL SCIENCE 11.8(2020):2260-2268. |
入库方式： OAI收割
来源：上海药物研究所
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