Nat Chem Biol: Is the itch unbearable? Chinese scientists have discovered a new way to cure the "itch"

Su Dongpo said: "It is easy to endure pain, but it is difficult to
endure itching.
" "Modern science has found that human perception of pain and itching is regulated by specific neural circuits, but many times, itching is a more unbearable sensation
than pain.
In the past, most of the drugs people used to relieve itching were antihistamines, but there are many skin diseases that cause itching that is non-histamine-dependent and cannot be relieved
by such drugs.

At 23:00 p.
m.
Beijing time on October 27, 2022, Professor Lei Xiaoguang of the School of Chemistry of Peking University cooperated with Professor Yang Yong of the Dermatology Hospital of the Chinese Academy of Medical Sciences and Jiang Daohua, a researcher from the Institute of Physics of the Chinese Academy of Sciences, to publish a paper online in the journal Nature Chemical Biology, revealing the mechanism of action of a small molecule inhibitor related to itching symptoms of skin diseases and confirming its potential
to treat a variety of skin diseases.

"Our new research has found a new way to relieve itching for various skin diseases such as atopic dermatitis, and also provides new ideas
for related drug development.
" Professor Lei Xiaoguang told
China Science News.

Olmsted syndrome (mutilating keratosis of the skin) is a rare genetic condition of the skin in which patients develop severe keratosis and hair loss with severe spontaneous itching
.
As early as 2012, Professor Yang Yong's team at the Chinese Academy of Medical Sciences discovered TRPV3 pathogenic mutations
including G573S in multiple cases of Olmsted syndrome.
TRPV3 is one of
the 6 members of the transient receptor potential vanilloid (TRPV) family.
Research related to the capsaicin receptor TRPV1 of the same family won the 2021 Nobel Prize
in Physiology or Medicine.

Further research showed that TRPV3 was also strongly associated
with pruritus caused by atopic dermatitis.
Atopic dermatitis is the largest chronic inflammatory disease among dermatological diseases, afflicting at least 250 million people worldwide

However, due to the lack of high affinity and high selectivity TRPV3 small molecule inhibitors, the research of TRPV3 as a potential therapeutic target has been lacking qualitative breakthroughs
.

In this study, the authors screened a molecular library containing 110,000 compounds through high-throughput drugs and finally identified the compound Trpvicin as a high-affinity TRPV3 antagonist.

Surprisingly, Trpvicin has no obvious inhibitory effect on other TRPV channel proteins of 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 experimentally found that Trpvicin could effectively relieve chronic and acute itching caused by dermatitis in mice; At the same time, Trpvicin was tested on animal models 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 mutations.

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

"Systemic pruritus due to atopic dermatitis has long been an unmet clinical need
.
This work provides a structural pharmacological basis
for the development of drugs related to these diseases by deeply understanding the pathogenic mechanism of TRPV3 mutations.
In the field of disease treatment in the future, we hope to see the lead drug molecules developed play a greater role
.
Lei Xiaoguang said
.

Dr.
Fan Junping, Distinguished Associate Researcher of Lei Xiaoguang's Research Group, School of Chemistry and Molecular Engineering, Peking University, Dr.
Hu Linghan from the Dermatology Hospital of the Chinese Academy of Medical Sciences, Yue Zongwei from 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.
Professor Lei Xiaoguang of Peking University, Professor Yang Yong of the Dermatology Hospital of the Chinese Academy of Medical Sciences and Professor Jiang Daohua of the Institute of Physics of the Chinese Academy of Sciences are the co-corresponding authors
.

Original source:

Fan， J.
， Hu， L.
， Yue， Z.
et al.
Structural basis of TRPV3 inhibition by an antagonist.
Nat Chem Biol (2022).
https：//doi.
org/10.
1038/s41589-022-01166-5.