PMID- 36427920
OWN - NLM
STAT- MEDLINE
DCOM- 20221129
LR  - 20221129
IS  - 1875-5364 (Electronic)
IS  - 1875-5364 (Linking)
VI  - 20
IP  - 11
DP  - 2022 Nov
TI  - Xenopus GLP-1-based glycopeptides as dual glucagon-like peptide 1 
      receptor/glucagon receptor agonists with improved in vivo stability for treating 
      diabetes and obesity.
PG  - 863-872
LID - S1875-5364(22)60196-1 [pii]
LID - 10.1016/S1875-5364(22)60196-1 [doi]
AB  - Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and 
      glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of 
      type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work 
      identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, 
      which showed decent hypoglycemic and body weight lowering activity. However, the 
      clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. 
      Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to 
      increased stability of secreted proteins, we rationally designed a panel of 
      O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual 
      agonists. One of the synthesized glycopeptides 1f was found to be equipotent to 
      xGLP/GCG-13 in cell-based receptor activation assays. As expected, 
      O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. 
      Importantly, chronic administration of 1f potently induced body weight loss and 
      hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism 
      and adiposity in both db/db and diet induced obesity (DIO) mice models. These 
      results supported the hypothesis that glycosylation is a useful strategy for 
      improving the in vivo stability of GLP-1-based peptides and promoted the 
      development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
CI  - Copyright (c) 2022 China Pharmaceutical University. Published by Elsevier B.V. All 
      rights reserved.
FAU - Li, Qiang
AU  - Li Q
AD  - Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of 
      Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China.
FAU - Yang, Qimeng
AU  - Yang Q
AD  - School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 
      221116, China.
FAU - Han, Jing
AU  - Han J
AD  - School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 
      221116, China; Key Laboratory of Early Prevention and Treatment for Regional High 
      Frequency Tumor, Ministry of Education, Guangxi Key Laboratory of Early 
      Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical 
      University, Nanning 530021, China.
FAU - Liu, Xiaohan
AU  - Liu X
AD  - Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of 
      Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China.
FAU - Fu, Junjie
AU  - Fu J
AD  - Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of 
      Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China. 
      Electronic address: jfu@jiangnan.edu.cn.
FAU - Yin, Jian
AU  - Yin J
AD  - Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of 
      Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China. 
      Electronic address: jianyin@jiangnan.edu.cn.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Chin J Nat Med
JT  - Chinese journal of natural medicines
JID - 101504416
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 0 (Receptors, Glucagon)
RN  - 0 (Glycopeptides)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Peptides)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Glucagon-Like Peptide 1/agonists/metabolism
MH  - Receptors, Glucagon/agonists/therapeutic use
MH  - Xenopus laevis/metabolism
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Glycopeptides/therapeutic use
MH  - Obesity/drug therapy
MH  - Hypoglycemic Agents/pharmacology
MH  - Peptides/pharmacology
OTO - NOTNLM
OT  - Diabetes
OT  - Glucagon
OT  - Glucagon-like peptide-1
OT  - O-GlcNAcylation
OT  - Obesity
EDAT- 2022/11/26 06:00
MHDA- 2022/11/30 06:00
CRDT- 2022/11/25 21:04
PHST- 2022/05/23 00:00 [received]
PHST- 2022/11/25 21:04 [entrez]
PHST- 2022/11/26 06:00 [pubmed]
PHST- 2022/11/30 06:00 [medline]
AID - S1875-5364(22)60196-1 [pii]
AID - 10.1016/S1875-5364(22)60196-1 [doi]
PST - ppublish
SO  - Chin J Nat Med. 2022 Nov;20(11):863-872. doi: 10.1016/S1875-5364(22)60196-1.