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Targeting beta-cell GLP-1 receptors has proven to be a viable strategy for the treatment of congenital hyperinsulinism (CHI), especially CHI due to loss of function mutations of KATP channels. Currently, Phase II clinical study of the GLP-1 receptor antagonist, Exendin-(9-39) has been successfully initiated. However, Exendin-(9-39) has a short half-life (less than 2 hrs), which limits its clinical applications. We are therefore trying to develop a long-acting GLP-1 receptor antagonist. AR-GLP1R-01 was synthesized based on chemical modification of Exendin-9-39. In order to test its efficacy in disease mouse models, SUR1 knockout mice was created by targeted deletion of abcc8 gene using CRISPR/Cas9. Exendin-9-39 and AR-GLP1R-01 were injected subcutaneously at doses of 216 nmol/kg. Plasma concentrations were determined by UPLC-MS at 30 min, 2 hrs and 10 hrs after injection. Plasma levels of Exendin-9-39 were 0.5 µM at 30 min after injection and were later undetectable at 2 and 10 hrs. In contrast, plasma levels of AR-GLP1R-01 were 2.0 µM at 30 min, peaked at 2 hrs, and remained at 2.9 µM after 10 hrs of injection. Compared to Exendin-(9-39), AR-GLP1R-01 has similar inhibitory effects in amino acid mixture-stimulated insulin secretion in perifused islets isolated from SUR1 knockout mice. In vivo experiments were performed by subcutaneous injection at a dosage of 216 nmol/kg twice a day at 10 am and 5 pm for 4 days. Similar to Exendin-9-39, AR-GLP1R-01 caused plasma glucose to increase 1 hr after injection. However, the glucose-increasing effects of AR-GLP1R-01 were maintained overnight before the 10 am injection for 4 days, while the effects of Exendin-9-39 failed to do so. In the separate experiments, the effects of AR-GLP1R-01 on glucose elevation can last for 24 hrs after a single dose injection. This early phase “proof of concept” study has shown that AR-GLP1R-01 is a long-acting GLP-1 antagonist and has potential to be developed into a once-a-day injection for the treatment of CHI. Disclosure Y.Yuan: Employee; Nanjing AscendRare Pharmaceutical Technology. H.Jiang: None. S.Meng: Employee; Nanjing AscendRare Pharmaceutical Technology. D.Han: Employee; Nanjing AscendRare Pharmaceutical Technology. Q.Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. M.Wang: Employee; Shandong Baixinyuan Pharmaceutical Co. LLC.. H.Li: Employee; Shandong Baixinyuan Pharmaceutical Co. LLC.. J.Li: None. C.Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology. Funding Shandong Innovation Project (2019JZZY021012)

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