Study on the hypoglycemic activity of betulinic acid derivatives by humanized TGR5 mice

The bile acid receptor TGR5 (Takeda G protein-coupled receptor 5) plays an important role in blood glucose homeostasis, energy expenditure and liver protection.

Bile acids are amphiphilic steroids, synthesized by the liver and stored in the gallbladder.

However, in the development of TGR5 agonists, the activity of many compounds on the mouse-derived TGR5 receptor (mTGR5) is significantly different from that on the human-derived TGR5 (hTGR5), but on the canine receptor (cTGR5).

Figure 1 Construction of ^{TGR5 H88Y} humanized mice through CRISPR-Cas9

At the same time, the researchers took the betulinic acid TGR5 agonist XYT528B as a starting point and modified the C3 position to obtain a carbamate structure 3d with better activity and more stable metabolism, and used docking to explain the reason for the increased activity, that is, the amino group.

Taking into account the inherent physical and chemical properties of triterpenoids, the researchers adopted the method of salt formation to obtain the compound 11d-Na (hTGR5 EC ₅₀ = 6.

Figure 2 Compound 11d-Na showed better activity on ^{TGR5 H88Y} in vitro and in vivo

In summary, this study clarifies that histidine at position 88 in mouse TGR5 (tyrosine at position 89 in human TGR5) is the key site that causes the difference in the activity of TGR5, and mTGR5 is matched by CRISPR/Cas9.

Ying Ying, a doctoral student from the Shanghai Institute of Materia Medica, Zhang Chenlu, a postdoctoral fellow at the Shanghai Institute of Materia Medica, and Guo Shimeng, a doctoral student jointly trained by Nanjing University of Chinese Medicine and Shanghai Institute of Materia Medica, are the co-first authors of the paper

Original link: https://pubs.