4 research outputs found
Novel insights into the dynamics behavior of glucagon-like peptide-1 receptor with its small molecule agonists
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Not AvailableAn 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.Not Availabl