Nature Chemical Biology: Mechanism of action of TRPV3 ion channel protein inhibitors and potential for the treatment of a variety of skin diseases

Transient receptor potential (TRP) channels are non-selective ion channels
that regulate the flow of cations across membranes.
TRP channels have been found to mediate various sensory responses, including heat, cold, pain, stress, vision, and taste
.
There are 6 members
of the transient receptor potential vanilloid (TRPV) subfamily.
Professor David Julius won the 2021 Nobel Prize
in Physiology or Medicine for his research on the capsaicin receptor TRPV1.

TRPV3, another ion channel protein of the same family as TRPV1 protein, plays a vital role
in skin physiology and pathological processes.
Previous studies have found that TRPV3 dysfunction can lead to a variety of skin conditions, such as Olmsted syndrome (dermatomic keratosis) and atopic dermatitis (AD).
Associated systemic itching, as well as hair loss
.
Olmsted syndrome is a rare skin disease in which patients can develop severe keratosis and hair loss, and 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 dermatology diseases, and the rash will affect most parts of the body, accompanied by intense, continuous itching, which seriously affects the quality of life
of patients.
According to WHO, at least 250 million people worldwide are currently affected
by AD.
The incidence of AD is 25% in children under 7 years of age and can reach 10%
in adults.
In 2012, Professor Yang Yong's team first discovered TRPV3 pathogenic mutations, including G573S, in cases of Olmsted syndrome and further explored TRPV3 is strongly associated
with itching of the skin caused by atopic dermatitis.
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 seriously hindered
.

On October 27, 2022, the Lei Xiaoguang Research Group of the Joint Center for Life Sciences and the collaborators Yang Yong/Jiang Daohua published a report in Nature Chemical Biology The journal Nature Chemical Biology published a paper online titled "Structural basis of TRPV3 inhibition by an antagonist.
"
The mechanism of action of small molecule inhibitors targeting TRPV3 ion channel protein was revealed and its potential for the treatment of
a variety of skin diseases was confirmed.

In this study, the authors found that exogenous overexpression of pathogenic mutants TRPV3_G573S lead to cell death, and used this phenomenon to perform high-throughput screening
of small molecule inhibitors.
By screening a molecular library containing 110,000 compounds, the authors finally identified the compound Trpvicin as a high-affinity TRPV3 antagonist (Figure 1).

Surprisingly, Trpvicin has no significant inhibitory effect on other TRPV channels of the same family, indicating that Trpvicin is a potentially subtype-selective TRPV3 Inhibitors
.

Figure 1.
High-throughput screening yielded the highly effective and specific TRPV3 inhibitor Trpvicin

Subsequently, the authors verified the effect of Trpvicin on animal models, and experimentally found that Trpvicin could effectively relieve acute and chronic itching 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 mutation (Fig 2）
。

Figure 2.
Trpvicin has shown good therapeutic effect in mouse models

To further investigate the mechanism by which Trpvicin functions, the authors used cryo-EM to resolve the high-resolution structure of the human-derived TRPV3-Trpvicin complex, revealing that Trpvicin binds to a reported TRPV In the pockets of ligand sites, Trpvicin was found to exert inhibition by stabilizing TRPV3 in the off state
.
Electrophysiological assays for binding point mutations, elucidating the molecular mechanism by which this new pocket can specifically bind to Trpvicin and elucidating in detail the molecular mechanism by which Trpvicin achieves subtype selectivity (Figure 3).

Figure 3.
The complex structure of TRPV3 with Trpvicin reveals binding pockets and mechanisms of action

The authors also resolved the complex structure of the pathogenic mutant TRPV3-G573S and Trpvicin, showing that the G573S mutation leads to channel pore expansion, resulting in sustained channel opening activity
.
Trpvicin also binds to sites in the central cavity of the G573S mutant, ultimately altering ion channel symmetry and blocking channels (Figure 4).

Figure 4.
Inhibition of TRPV3 pathogenic mutant G573S by Trpvicin

In summary, this study explores the mechanism of Trpvicin 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
.
In the past, people used antihistamines to relieve itching, but many itching symptoms caused by dermatitis are not directly related to histamine, resulting in a long-term lack of effective drugs
for such diseases.
This study provides new ideas
for the development of itch-related drugs.

Dr.
Fan Junping, Distinguished Associate Researcher of Lei Xiaoguang's Research Group, School of Chemistry, Peking University, Dr.
Hu Linghan, Hospital of Dermatology, Chinese Academy of Medical Sciences, Yue Zongwei, Postdoctoral Fellow of Lei Xiaoguang's Research Group, and Dr.
Liao Daohong of Sunshine Anjin Company 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, Chinese Academy of Sciences are the co-corresponding authors
.
This work was supported by the National Natural Science Foundation of China, the Key Research and Development Program of the Ministry of Science and Technology, Beijing The "Outstanding Young Scientist Program", Beijing National Research Center for Molecular Sciences, Joint Center for Life Sciences and other major scientific research projects and research institutions in many countries
.
We would also like to thank Peking University and the Institute of Biophysics of the Chinese Academy of Sciences for their cryo-EM support
for this study.

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