Shanghai Institute of Materia Medica cooperates to discover new target of diabetes CREB/CRTC2 protein-protein interaction inhibitor lead compound

At present, there are about 120 million diabetic patients in China, and traditional diabetes drugs are not effective in reducing fasting blood sugar
.

The abnormal activity of hepatic gluconeogenesis is one of the main reasons for the persistently high blood sugar level in diabetic patients, and it is also the main culprit of fasting hyperglycemia in patients
.

Hepatic gluconeogenesis mediated by the key CREB/CRTC2 transcriptional complex in the liver is one of the main pathways of the body's blood glucose elevation
.

CREB/CRTC2 protein-protein interaction inhibitors can regulate the expression of downstream gluconeogenesis-related genes and reduce fasting blood glucose by inhibiting gluconeogenesis
.

Recently, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Fudan University and Nanjing University of Traditional Chinese Medicine have made important progress in the research of CREB/CRTC2 protein-protein interaction inhibitors, a new target for diabetes
.

The result was published in the internationally renowned journal Nature Communications on January 11, 2022 under the title "A propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex"
.

In this study, the researchers verified for the first time that the main component of Brazilian propolis, artepillin C (artepillin C), can inhibit the CREB/CRTC2 protein-protein interaction, and at the same time reduce fasting blood glucose and increase insulin in db/db mice Sensitivity, lowers blood lipid levels in the body
.

Through in vitro and in vivo experiments, it was verified that the natural product Apideline C binds to CREB, blocks the CREB/CRTC2 protein-protein interaction, regulates the expression of gluconeogenesis-related genes, and then exerts the therapeutic effect of reducing fasting blood glucose
.

In order to improve the inhibitory effect and druggability of the natural product Apideline C on the CREB/CRTC2 protein-protein interaction, the researchers comprehensively used a variety of structural optimization and design strategies in medicinal chemistry to conduct the CREB/CRTC2 protein-protein interaction inhibitor.
Structure-activity relationship study and pharmacological activity evaluation
.

Through multiple rounds of structural optimization, it was found that the lead compound A57 targeting the CREB/CRTC2 protein-protein interaction inhibitor has a strong inhibitory effect on the CREB/CRTC2 protein-protein interaction with IC50 reaching 0.
74 μM, which is a natural product of apidiline 30 times the inhibitory activity of C; Compound A57 significantly inhibited the transcription levels of gluconeogenesis rate-limiting enzyme genes Pck1 and G6pc; oral administration significantly reduced fasting blood glucose and blood lipid levels in db/db mice, but not in CRTC2 KO mice The glucose activity further verified the hypoglycemic mechanism of the lead compound A57
.

The research work provides a new target and a new treatment strategy for diabetic patients with poor fasting blood glucose treatment effect.
The discovery of the lead compound A57 has laid a research foundation for the development of class I diabetes drugs with China's independent intellectual property rights
.

Chen Yaqiong from Fudan University and Wang Jiang from Shanghai Institute of Materia Medica, Chinese Academy of Sciences are the co-first authors of the article; Professor Liu Xun from Fudan University, Professor Liu Hong from Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Professor Hu Lihong from Nanjing University of Traditional Chinese Medicine are the joint correspondents of the article author
.

The research was supported by the National Natural Science Foundation of China, the Pilot Project of the Chinese Academy of Sciences, and the Fund of the Shanghai Municipal Science and Technology Commission
.

Full text link https://