-
Tytuł:
-
Rational design and evaluation of GLP-1 derivative for treating hyperglycemia combined with overexercise-induced myocardial injury.
-
Autorzy:
-
Wang Y; School of Physical Education, Shandong Normal University, Jinan 250358, Shandong, PR China.
Xia Z; Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, PR China.
Xie H; School of Athletic Training, Guangzhou Sport University, Guangzhou 510000, Guangdong, PR China. Electronic address: .
Dong J; School of Physical Education, Shandong Normal University, Jinan 250358, Shandong, PR China. Electronic address: .
-
Źródło:
-
Life sciences [Life Sci] 2021 May 01; Vol. 272, pp. 119030. Date of Electronic Publication: 2021 Jan 13.
-
Typ publikacji:
-
Journal Article
-
Język:
-
English
-
Imprint Name(s):
-
Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
-
MeSH Terms:
-
Glucagon-Like Peptide 1/*analogs & derivatives
Glucagon-Like Peptide 1/*pharmacology
Hyperglycemia/*drug therapy
Animals ; Chromatography, Liquid ; Diabetes Mellitus, Experimental/drug therapy ; Glucagon-Like Peptide-1 Receptor/metabolism ; Glucose/metabolism ; Hypoglycemic Agents/pharmacology ; Liraglutide/pharmacology ; Male ; Mice ; Mice, Inbred DBA ; Obesity/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucagon/metabolism ; Tandem Mass Spectrometry
-
Contributed Indexing:
-
Keywords: GLP-1; Hyperglycemia; Myocardial injury; Overexercise; Thrombin
-
Substance Nomenclature:
-
0 (Glucagon-Like Peptide-1 Receptor)
0 (Hypoglycemic Agents)
0 (Receptors, Glucagon)
839I73S42A (Liraglutide)
89750-14-1 (Glucagon-Like Peptide 1)
IY9XDZ35W2 (Glucose)
-
Entry Date(s):
-
Date Created: 20210116 Date Completed: 20210402 Latest Revision: 20210402
-
Update Code:
-
20240105
-
DOI:
-
10.1016/j.lfs.2021.119030
-
PMID:
-
33453242
-
Aims: To design and evaluate the anti-hyperglycemia and overexercise-induced myocardial injury efficacies of a novel long-acting glucagon-like peptide-1 (GLP-1)-based therapeutic peptide in rodent animals.
Main Methods: Here, we designed and prepared a new pro-drug, termed RYHSB-1, which was connected by a mutated GLP-1(A8G) and an albumin binding peptide via a protease-cleavable linker. Moreover, isothermal titration calorimetry (ITC) was applied to detect its binding affinity for HSA. GLP-1 release assay was conducted in mouse serum in vitro and quantified using LC-MS/MS method. Modified intraperitoneal glucose tolerance test (IPGTT), chronic efficacies study in rodent animals with overexercise-induced myocardial injury were subjected to evaluate the druggability of RYHSB-1.
Results: RYHSB-1 with purity over 99% was prepared and ITC measurement demonstrated high binding affinity for HSA with KD of 0.06 μM. Protease cleavage assay demonstrated slowly controlled-release of transient GLP-1 from RYHSB-1 under the hydrolysis catalyzed by thrombin in vitro. Moreover, IPGTT showed clearly dose-dependent glucose-lowering efficacies of RYHSB-1 within 0.1-0.9 mg/kg. The prolonged anti-diabetic efficacy of RYHSB-1 was further assessed via multiple IPGTTs and hypoglycemic duration test. Furthermore, long-term administration of RYHSB-1 in diabetic mice achieved promising efficacies on hyperglycemia and overexercise-induced myocardial injury.
Significance: RYHSB-1 holds outstanding pharmaceutical potential as an anti- overexercise-induced myocardial injury drug. The strategy of albumin-conjugation also could be applied to other active peptides develop long effecting therapeutic drugs.
(Copyright © 2021. Published by Elsevier Inc.)
