苦瓜多肽类似物的分子构建、降糖活性和作用机制研究

苦瓜具有较好的降血糖活性,本课题选择具有确切降糖活性的苦瓜多肽MC62和MC21为先导物，采用单模微波辅助固相合成技术，快速合成得到系列苦瓜多肽类似物。先采用氨基酸探针逐点置换先导多肽链，构建完整的氨基酸多位点组合扫描矩阵，并在活性较好的多肽链上做进一步的构象限制设计，使得所构建的肽库在一级结构和二级结构上具有多样性，可充分考察各肽链氨基酸序列变化以及空间构象变化和降糖活性之间的关系。前期工作首次发现合成得到的部分苦瓜多肽类似物表现出显著的抗胰岛β细胞凋亡的效果，具有较好的胰岛细胞保护功能。在此基础上，从整体动物、细胞和分子不同层面上全面探讨苦瓜多肽类似物的降血糖作用机制。通过本项目的深入研究，有望获得兼具降糖活性和胰岛保护功能的全新作用机制的外源性降血糖短肽，揭示苦瓜多肽类似物降血糖活性起效的物质基础和作用机制，为苦瓜降糖多肽类似物的研发及临床应用奠定理论基础。

Bitter gourd (Momordica charantia) is known to have definite hypoglycemic effects. Peptides extracted from bitter gourd have been considered widely as the main effective parts for its hypoglycemic effects. Bitter gourd peptides MC62 and MC21 with definite hypoglycemic activity were chosen as the lead compounds in this project. Single-mode microwave-assisted solid phase synthesis technology is applied for the rapid synthesis of the peptide analogs..Firstly, an amino acid probe was introduced for the replacement of the amino acids in the peptide chain point-by-point, followed with activity screening, to achieve the information of the key amino acids in the peptide chain. These substitution methods constructed a multi-Positional Scanning matrix library of amino acids. Then the peptides with better activity were selected for the conformational restriction design. The methods will completely reveal the relationships between the hypoglycemic activity and the changes in amino acids or the spatial configuration of the peptide chain..In our previous work, it was found that some of the synthesized bitter gourd peptide analogs could protect pancreatic β-cell from apoptosis significantly for the first time. Based on these findings, the comprehensive study of the hypoglycemic mechanism of bitter melon peptides will be developed from the whole animal, cellular and molecular levels respectively. Through the in-depth study of this project, it is expected to obtain short exogenous hypoglycemic peptides with both hypoglycemic activity and pancreatic protection features of the new action mechanisms.The work will provide theoretical basis for the development and clinical application of bitter gourd hypoglycemic peptides, improving the overall existing research level of the hypoglycemic peptides.