CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.
J Med Chem. 2021 Aug 26;64(16):12181-12199. doi: 10.1021/acs.jmedchem.1c00851. Epub 2021 Aug 18.
Takeda G protein-coupled receptor 5 (TGR5) is a promising target for treating metabolic syndrome and inflammatory diseases. Herein, we identified a new series of betulinic acid derivatives as potent TGR5 agonists, which show remarkable activity on human (h) and canine (c) TGR5 but exhibit unpromising activity on murine (m) TGR5. Species difference was also observed with many other reported TGR5 agonists. Therefore, we screened 29 amino acids which were conserved in hTGR5 and cTGR5 but different in mTGR5 and found a key amino acid, H88 in mTGR5 (Y89 in hTGR5), which contributed to the species difference. With the CRISPR/Cas9 system, the mTGR5 mutation was introduced into mice, and the optimized compound displayed a significant glucose-lowering effect and stimulated GLP-1 and insulin secretion in TGR5 mice but not in wild-type animals. Taken together, our study provides a useful tool to bridge the gap of species difference and discovers a potent TGR5 agonist for further investigation.
武田 G 蛋白偶联受体 5（TGR5）是治疗代谢综合征和炎症性疾病的有前途的靶点。在此，我们鉴定了一系列新的桦木酸衍生物，它们是有效的 TGR5 激动剂，对人（h）和犬（c）TGR5 具有显著活性，但对鼠（m）TGR5 活性不佳。许多其他报道的 TGR5 激动剂也观察到了种属差异。因此，我们筛选了 29 个在 hTGR5 和 cTGR5 中保守但在 mTGR5 中不同的氨基酸，发现了 mTGR5 中的一个关键氨基酸 H88（hTGR5 中的 Y89），这导致了种属差异。通过 CRISPR/Cas9 系统，将 mTGR5 突变引入小鼠，优化后的化合物在 TGR5 小鼠中显示出显著的降血糖作用，并刺激 GLP-1 和胰岛素分泌，但在野生型动物中没有。总之，我们的研究提供了一个有用的工具来弥合种属差异，并发现了一种有效的 TGR5 激动剂，可进一步研究。
