小分子化合物多西环素降糖作用关键靶点GLP-1受体的确定及其促胰岛素分泌机制研究

GLP-1受体激动剂（GLP-1RA）是目前较为理想的抗糖尿病药物，但上市产品均为大分子肽类制剂，有需要注射给药等局限性，降低了患者的依从性。而小分子GLP-1RA具有易于开发为口服制剂、使用便利等前景，使其成为新型降糖药物的研发重点。多西环素（DX）是一种临床使用多年的可口服小分子广谱抗生素。我们发现DX具有与GLP-1RA相似的抗糖尿病作用特点，同时DX和GLP-1R分子对接成功也高度提示GLP-1R是DX的关键作用靶点。此外，我们的研究表明抑制Kv通道极有可能是DX产生促胰岛素分泌作用的关键环节。本项目拟在此基础上对DX/GLP-1R/AC/cAMP/Kv通道这一中心调控路线开展深入研究，明确DX是一种新型的小分子GLP-RA及其促胰岛素分泌机制，为探索以DX为基础的新型小分子GLP-1RA类抗糖尿病药物提供理论线索和实验依据。同时，也为进一步扩大和优化DX的临床应用提供药理学依据。

Glucagon-like peptide-1 receptor agonists(GLP-1RA) become the attractive options for the treatment of diabetes because of their hypoglycemic effects and their cardiovascular benefits. However, most of the GLP-1RAs are macromolecular peptides and the way of injection administration reduces patients’ compliance. Therefore the research and development of new hypoglycemic drugs focus on small molecule GLP-1RA，which can be administrated through oral and easy to be used. Doxycycline (DX) is an oral small molecule broad-spectrum antibiotic which has been used for many years. We found that DX has similar antidiabetic effect as GLP-1RA, and the successful molecular docking of DX and glucagon-like peptide-1 receptor(GLP-1R) highly suggests that GLP-1R is the key target of DX. In addition, our study shows that inhibition of Kv channel is likely to be the key point for DX to promote insulin secretion. Our reasearch project aim to focus on the DX/GLP-1R/AC/cAMP/Kv pathway and to further clarify that DX is a new small molecule GLP-1RA and its mechanism of promoting insulin secretion. The results will provide the clues and experimental evidence for the exploration of DX-based new small molecule GLP-1RA antidiabetic drugs and pharmacological basis for further expanding and optimizing the clinical application of DX.