PMID- 30795583
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20200225
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 24
IP  - 4
DP  - 2019 Feb 21
TI  - Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent 
      Antidiabetic Effects.
LID - 10.3390/molecules24040779 [doi]
LID - 779
AB  - Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as treatment 
      options for type 2 diabetes mellitus (T2DM). Here, we designed a high-throughput 
      GLP-1R extracellular domain (ECD)-based system that enabled the screening of 
      high-potency receptor-biased GLP-1R agonists demonstrating new pharmacological 
      virtues. Firstly, six 12-mer peptides (termed PEP01(-)06), screened from a large 
      phage displayed peptide library were fused to the N-terminus of Exendin-4 (29(-)39) 
      to generate PEP07(-)12. By the use of four lysine-altered PEP07 (PEP13(-)16) as the 
      starting point, a series of fatty chain conjugates (PEP17(-)20) were synthesized 
      and evaluated by in vitro GLP-1R-based cell assays. In addition, the acute and 
      long-term in vivo effects on diet-induced obesity (DIO) mice were further 
      evaluated. All four conjugates showed good receptor activation efficacy, and 
      PEP20 was selected to undergo further assessment. Preclinical experiments in DIO 
      mice demonstrated that PEP20 had significant insulinotropic activities and 
      glucose-lowering abilities. Moreover, a prolonged antidiabetic effect of PEP20 
      was also observed by the hypoglycemic test in DIO mice. Furthermore, long-term 
      treatment with PEP20 achieved beneficial effects on the food intake, weight gain, 
      hemoglobin A1C (HbA1C) lowering activity, and glucose tolerance compared with the 
      control and was similar to the Liraglutide. In conclusion, PEP20, a GLP-1R 
      ECD-biased agonist, may provide a novel therapeutic approach to T2DM.
FAU - Zhong, Xia
AU  - Zhong X
AD  - College of Life Science and Technology, Jinan University, Guangzhou 510000, 
      China. x_zhong@outlook.com.
AD  - Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. x_zhong@outlook.com.
FAU - Chen, Zhu
AU  - Chen Z
AD  - Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. Zchen@163.com.
AD  - East China University of Science and Technology, Shanghai 200000, China. 
      Zchen@163.com.
FAU - Chen, Qiong
AU  - Chen Q
AD  - Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. qchen0862@yeah.net.
FAU - Zhao, Wei
AU  - Zhao W
AD  - Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. zwei1008@163.com.
FAU - Chen, Zhi
AU  - Chen Z
AD  - East China University of Science and Technology, Shanghai 200000, China. 
      Paulchan121@outlook.com.
LA  - eng
PT  - Journal Article
DEP - 20190221
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Fatty Acids)
RN  - 0 (Glp1r protein, mouse)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Glycoconjugates)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Peptide Library)
RN  - 0 (Peptides)
RN  - 9P1872D4OL (Exenatide)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - Diet, High-Fat/adverse effects
MH  - Exenatide/genetics/metabolism
MH  - Fatty Acids/chemistry
MH  - Gene Expression Regulation
MH  - Glucagon-Like Peptide-1 Receptor/*agonists/genetics/metabolism
MH  - Glucose Tolerance Test
MH  - Glycoconjugates/chemistry/metabolism/*pharmacology
MH  - Hyperglycemia/*drug therapy/etiology/genetics/metabolism
MH  - Hypoglycemic Agents/chemistry/metabolism/*pharmacology
MH  - Insulin-Secreting Cells/*drug effects/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Obesity/*drug therapy/etiology/genetics/metabolism
MH  - Peptide Library
MH  - Peptides/chemistry/metabolism/pharmacology
MH  - Protein Binding
MH  - Rats
MH  - Structure-Activity Relationship
PMC - PMC6412877
OTO - NOTNLM
OT  - Exendin-4
OT  - Glucagon-like peptide-1 receptor
OT  - antidiabetic effects
OT  - extracellular domain
OT  - fatty chain
COIS- The authors declare no conflicts of interest.
EDAT- 2019/02/24 06:00
MHDA- 2019/06/14 06:00
PMCR- 2019/02/21
CRDT- 2019/02/24 06:00
PHST- 2019/01/16 00:00 [received]
PHST- 2019/02/15 00:00 [revised]
PHST- 2019/02/15 00:00 [accepted]
PHST- 2019/02/24 06:00 [entrez]
PHST- 2019/02/24 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2019/02/21 00:00 [pmc-release]
AID - molecules24040779 [pii]
AID - molecules-24-00779 [pii]
AID - 10.3390/molecules24040779 [doi]
PST - epublish
SO  - Molecules. 2019 Feb 21;24(4):779. doi: 10.3390/molecules24040779.