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Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor

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Title Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor
Not Available
 
Creator Khyati Girdhar
Shilpa Thakur
Pankaj Gaur
Abhinav Choubey
Surbhi Dogra
Budheswar Dehury
Sunil Kumar
Bidisha Biswas
Durgesh Kumar Dwivedi
Subrata Ghosh
Prosenjit Mondal
 
Subject GLP1R
GLP1R agonist
pancreatic beta cells
small molecule GLP1R agonist
 
Description Not Available
An absolute or relative deficiency of pancreatic β-cells mass and functionality is a crucial pathological feature common to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Glucagon-like-peptide-1 receptor (GLP1R) agonists have been the focus of considerable research attention for their ability to protect β-cell mass and augment insulin secretion with no risk of hypoglycemia. Presently commercially available GLP1R agonists are peptides that limit their use due to cost, stability, and mode of administration. To address this
drawback, strategically designed distinct sets of small molecules were docked on GLP1R ectodomain and compared with previously known small molecules GLP1R agonist. One of the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxaline) displays stable binding with GLP1R, induces GLP1R internalization and increasing cAMP levels. PK2 also increases insulin secretion in the INS-1 cells. The oral administration of PK2 protects against diabetes induced by multiple low-dose streptozotocin
(STZ) administration by lowering high blood glucose levels. Similar to GLP1R peptidic agonists, treatment of PK2 induces β-cell replication and attenuate β-cell apoptosis in STZ treated mice. Mechanistically, this protection was associated with decreased thioredoxin interacting protein (TXNIP) expression, a potent
inducer of diabetic β-cell apoptosis and dysfunction. Together, this report describes a small molecule, PK2, as an orally active non peptidic GLP1R agonist that has efficacy to preserve or restore functional β-cell mass.
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Date 2022-05-28T09:04:07Z
2022-05-28T09:04:07Z
2022-03-01
 
Type Research Paper
 
Identifier Khyati Girdhar, Shilpa Thakur, Pankaj Gaur, Abhinav Choubey, Surbhi Dogra, Budheswar Dehury, Sunil Kumar, Bidisha Biswas, Durgesh Kumar Dwivedi, Subrata Ghosh, Prosenjit Mondal (2022). Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor, Journal of Biological Chemistry, 298(5), 101889, ISSN 0021-9258, https://doi.org/10.1016/j.jbc.2022.101889.
Not Available
http://krishi.icar.gov.in/jspui/handle/123456789/72405
 
Language English
 
Relation Not Available;
 
Publisher Elsevier