Author's interpretation| Zeng Kewu/Tu Pengfei of Peking University revealed a new target of neuroinflammation regulated by the active ingredient of Chinese medicine Mustang

At present, China is seriously aging and the population suffering from neurodegenerative diseases is increasing, but there is currently no effective treatment strategy
for such diseases.
If the central nervous system is compared to a city, then the microglia in the brain are like "soldiers" who defend the nervous system, responsible for resisting the invasion
of external pathogens.
However, the war is brutal, and the continuous work of microglia can lead to their abnormal activation, induce neuroinflammation and damage surrounding neurons, and ultimately promote the development
of neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
However, there are currently no effective therapeutic drugs for this pathological process
.

In recent years, many natural active molecules derived from traditional Chinese medicine have shown good anti-neuritic activity ^[1], which has great potential for
new drug development.
Therefore, how to find highly active anti-neuroinflammatory drugs from traditional Chinese medicine will help open up a new direction for the treatment of current neurodegenerative diseases; At the same time, the use of effective natural active molecules as probes may also discover new disease treatment targets, so it has aroused a wide range of research interest ^[2].

On August 12, 2022, Zeng Kewu/Tu Pengfei from the State Key Laboratory of Natural Medicine and Biomimetic Drugs of Peking University published a paper entitled " Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy deeply reveals the active ingredient of Chinese medicine Mustang chasing lactone B ( Eupalinolide B (EB) allosteric regulation target USP7, thereby exerting a molecular mechanism
of anti-neuroinflammation and improvement of neurodegenerative diseases through the Keap1/Nrf2 signaling pathway.

The researchers first found that Brona chasingolone B (EB) has significant anti-neuroinflammatory activity, in order to reveal the direct action target of EB, a biotin-modified EB molecular probe was constructed, and the human proteome chip was used to screen out the target of EB to exert anti-neuroinflammatory effect Deubiquitinase 7 (USP7).

SUBSEQUENTLY, THE CRYSTAL STRUCTURE OF THE COMPLEX BETWEEN EB AND THE USP7 HUBL DOMAIN WAS ANALYZED, AND IT WAS FOUND THAT EB COVALENTLY BOUND TO 576 CYSTEINE IN THE USP7 HUBL domain with its α,β-unsaturated carbonyl.
and are tightly bonded by hydrogen bonds and van der Waals forces in the negatively charged chamber of the USP7 HUBL
.
The researchers further found that EB effectively inhibited the USP7 to specific substrate protein Keap1 by inducing conformational changes in the USP7 HUBL region, which in turn caused USP7 to be in an "over-open" inactivation state Deubiquitination effect
.
This triggered a significant degradation of the substrate protein Keap1, which in turn promoted downstream Nrf2 nuclear metastasis and activated the downstream anti-inflammatory proteins HO-1 and NQO1 and other expressions, exert anti-neuroinflammatory effects
.
In addition, the researchers also investigated the therapeutic effect of EB on neuroinflammation-related senile dementia and Parkinson's disease, and found that EB can significantly improve the learning and memory ability of dementia mice and improve motor coordination in Parkinson's disease mice through anti-neuroinflammation (Figure 1).
）
。

This study demonstrates a new target for the treatment of neurodegenerative diseases caused by inflammation, and also provides a lead drug molecule with great development potential, which is of great significance for promoting the development of innovative drugs for neurodegenerative diseases ^[3]
.

Zhang Xiaowen, a doctoral student at Peking University School of Pharmacy, and Feng Na, a postdoctoral fellow (currently an assistant researcher at the Institute of Biophysics, Chinese Academy of Sciences), are the co-first authors of this paper, and researchers Zeng Kewu and Tu Pengfei of the State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmacy Professor is the co-corresponding author
of this paper.
The research was supported
by the National Natural Science Foundation of China and the National Key Research and Development Program.

References:

[1] J.
Eder, R.
Sedrani, C.
Wiesmann, The discovery of first-in-class drugs: origins and evolution.
Nat Rev Drug Discov 13, 577-587 (2014).

[2] R.
Dantzer, J.
C.
O'Connor, G.
G.
Freund, R.
W.
Johnson, K.
W.
Kelley, From inflammation to sickness and depression: when the immune system subjugates the brain.
Nat Rev Neurosci 9, 46-56 (2008).

[3] R.
Niranjan, Recent advances in the mechanisms of neuroinflammation and their roles in neurodegeneration.
Neurochem Int 120, 13-20 (2018).

Zeng Kewu, researcher and doctoral supervisor, was selected for the high-level talent program
of the Ministry of Education.
He proposed "Chemical Biology of Traditional Chinese Medicine", has long been committed to the discovery of natural active molecular probes and drug target identification research, and has published a series of research papers in international academic journals such as PNAS, Sci Adv, ACS Cent Sci, ACS Nano, STTT, etc He has more than 60 papers, and his research results have been selected as "China's Top Ten Medical Progresses" in 2017, and he currently serves as a director, member and youth committee member of academic groups such as the World Federation of Chinese Medicine Societies, the Chinese Society of Integrative Medicine, and the Chinese Pharmacological Society
.