Lei Xiaoguang's research group and collaborators in the School of Chemistry discovered a new way to cure "itch"

Su Dongpo said: "It's easy to endure pain, but it's hard to
endure itching.
" Modern science has found that both pain and itching are regulated by specific neural circuits, but many times, itching is a feeling
that is more unbearable than pain.
In the past, most of the drugs used to relieve itching were antihistamines, but there were many skin diseases caused by itching that were non-histamine-dependent and could not be relieved
by such drugs.

TRPV3 is one of the 6 members of the transient receptor potential vanilloid channel (TRPV) family, and the research related to the capsaicin receptor TRPV1 of the same family has won the 2021 Nobel Prize
in Physiology or Medicine.
Previous studies have found that TRPV3 dysfunction can lead to a variety of skin diseases, such as Olmsted syndrome (mutilating keratosis cutaneous), systemic pruritus associated with atopic dermatitis (AD), and hair loss
.
Olmsted syndrome is a rare class of skin diseases in which patients can have severe keratosis and alopecia, and it is the only human genetic disease with spontaneous itching found so far, and is a good model
for studying itching.
In addition, AD is the largest chronic inflammatory disease in the patient population of dermatological diseases, and the rash can affect most parts of the body, accompanied by intense, persistent itching, which seriously affects the quality of life of patients
.
According to WHO, at least 250 million people worldwide are currently affected by AD
.
However, the lack of high-affinity and selective TRPV3 small molecule inhibitors has severely hampered
TRPV3 research as a potential therapeutic target.

On October 27, 2022, 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 and collaborators Professor Yang Yong of the Dermatology Hospital of the Chinese Academy of Medical Sciences / Researcher Jiang Daohua of the Institute of Physics, Chinese Academy of Sciences The research group published a paper entitled "Structural basis of TRPV3 inhibition by an antagonist" online in the journal Nature Chemical Biology, revealing the mechanism of action of small molecule inhibitors targeting TRPV3 ion channel protein and confirming its potential
to treat itching symptoms in a variety of skin diseases.

Figure 1 Schematic diagram of the mechanism by which Trpvicin inhibits TRPV3

In this study, the authors identified the compound Trpvicin as a high-affinity TRPV3 antagonist
by screening a molecular library of 110,000 compounds through high-throughput drug screening.
Surprisingly, Trpvicin has no obvious inhibitory effect on other TRPV channel proteins in the same family and a variety of other types of proteins in the human body, indicating that Trpvicin is a highly selective TRPV3 inhibitor
.

Subsequently, the authors verified the effect of Trpvicin on animal models, and experiments found that Trpvicin can effectively relieve chronic and acute itching caused by dermatitis in mice; At the same time, Trpvicin was tested using the animal model of hair loss established in the laboratory, and it was found that Trpvicin also had a good therapeutic effect
on hair loss caused by TRPV3 mutation.

In order to further investigate the mechanism of Trpvicin's function, the authors used cryo-EM to analyze the high-resolution electron microscopy structure of human TRPV3-Trpvicin complex, and elaborated the molecular mechanism of Trpvicin to achieve isotype selectivity
.

In summary, this study explores the mechanism of Trpvicin's inhibition of TRPV3, which provides a structural basis
for in-depth understanding of the pathogenic mechanism of TRPV3 mutation and related drug development.
AD-induced systemic pruritus has long been an unmet clinical need, and this study provides new ideas
for pruritus-related drug development.

Dr.
Fan Junping, a distinguished associate researcher in Lei Xiaoguang's research group, Dr.
Hu Linghan from the Dermatology Hospital of the Chinese Academy of Medical Sciences, Yue Zongwei, a postdoctoral fellow in Lei Xiaoguang's research group, and Dr.
Liao Daohong from Sunshine Anjin Biomedical Technology Co.
, Ltd.
are co-first authors
.
Guo Fusheng and Ke Han, doctoral students in Lei Xiaoguang's research group, also contributed
to the research.
Lei Xiaoguang, Yang Yong and Jiang Daohua co-corresponding authors
.
This work has been supported
by the National Natural Science Foundation of China, the Key Research and Development Program of the Ministry of Science and Technology, the Beijing Outstanding Young Scientist Program, the Beijing National Research Center for Molecular Sciences, the Peking University-Tsinghua Joint Center for Life Sciences, and other major scientific research projects and research institutions in many countries.
Peking University and the Institute of Biophysics of the Chinese Academy of Sciences provided cryo-EM support
for this study.