Lei Xiaoguang's team completed the first biomimetic total synthesis and biological mechanism study of the natural product Fargesone A

As an important member of the nuclear receptor family, Farnesoid X receptor FXR (Farnesoid X Receptor) is highly expressed in the liver and small intestine, and has an important regulatory function
for maintaining metabolic homeostasis in vivo.
A large number of in vitro and in vitro biological function studies have confirmed that FXR is a valuable pharmacological target, so FXR has become one of
the hot targets for drug development of metabolic diseases since its discovery.
However, so far, only cholic acid-derived obeticholic acid OCA (Obeticholic acid) as an agonist of FXR has been approved by the FDA for the treatment of primary biliary cirrhosis, and the treatment of non-alcoholic fatty liver disease is in the clinical phase III.
stage, but OCA has experienced many side effects
including severe itching in multiple clinical trials 。 In view of the important biological functions of FXR and the lack of regulators with clinical transformation value, it is of great scientific significance
to develop FXR modulators with novel chemical backbones as drug lead small molecules, in order to derive safer and more effective FXR target drugs to meet the current needs of clinical practice.

Recently, Professor Lei Xiaoguang's research group from the School of Chemistry and Molecular Engineering of Peking University and the Peking University-Tsinghua Joint Center for Life Sciences published an online report entitled "Biomimetic total synthesis and the biological evaluation of natural product (–)-fargesone A as a novel FXR agonist" online in the journal JACS Au, the core journal of the American Chemical Society In the research paper, it was found that the natural product Fargesone A is a novel FXR nuclear receptor small molecule agonist with pharmacological activity in the treatment of liver diseases, and completed the efficient and biomimetic total synthesis of this natural product for the first time (Figure 1).

Fig.
1 Total synthesis and biological mechanism study of the natural product Fargesone A

The research team used this feature to design a protein-level microbead-based alpha Screen high-throughput screening system, efficiently screened a molecular library containing 2700 natural products, and finally identified Fargesone A, a natural product derived from traditional Chinese medicine Xinyi, as a selective FXR agonist with high affinity, which can efficiently activate FXR at the protein and cellular levels
。

In order to solve this problem, the direct separation rate of Fargesone A from plants is extremely low, and Lei Xiaoguang's team completed the first asymmetric total synthesis
of Fargesone A and two natural products of its family in a 9-step reaction, starting from commercially available raw materials.
This route uses biomimetic synthesis strategy to synthesize a large number of target natural products, which solves the problem of lack of natural product sources for subsequent biological research (Figure 2).

Figure 2 Efficient, biomimetic fully synthetic route of Fargesone A

Lei Xiaoguang's team confirmed the pharmacokinetic parameters of Fargsone A in mice, and confirmed that Fargsone A can induce the expression of a series of FXR target genes in mouse animal models of bile duct ligation (BDL), and has a good effect
on liver inflammation and fibrosis.

In summary, Lei Xiaoguang's team discovered a novel skeleton FXR natural product agonist Fargesone A through high-throughput screening, which confirmed its good hepatoprotective effect as an FXR agonist through a series of biological activity tests, and developed its first efficient asymmetric total synthesis route
.
It can be expected that derivative optimization of druggability of Fargesone A to create other derivatives with optimized structures will potentially provide an effective avenue
for the development of new drug candidates for the treatment of FXR-associated liver disease.

The co-first authors of the paper are Guo Fusheng, a doctoral student at the Institute of Advanced Interdisciplinary Studies of Peking University/Peking University-Tsinghua Joint Center for Life, and Chen Kaiqi, a doctoral student at the School of Chemistry, Peking University, and the corresponding author is Lei Xiaoguang
.
Dong Haoran, Hu Dachao, Gao Yihui and Liu Chenjue, doctoral students of Lei Xiaoguang's research group, also made important contributions
to the research.
Professor Surat Laphookhieo from Mae Fah Luang University in Thailand contributed to this paper
.
This work has been supported
by major scientific research projects and research institutions in many countries, such as the National Natural Science Foundation of China (especially the China-Thailand International Cooperation Program), the Beijing "Outstanding Young Scientist Program" project, the Beijing National Research Center for Molecular Sciences, and the Peking University-Tsinghua Joint Center for Life Sciences.