Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, China.
University of Chinese Academy of Sciences, Beijing, China.
Br J Pharmacol. 2021 Apr;178(7):1669-1683. doi: 10.1111/bph.15390. Epub 2021 Feb 26.
Itching is the most frequent pathology in dermatology that has significant impacts on people's mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology.
FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay.
An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC ) of 12.43 μM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed.
By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti-pruritus drugs.
瘙痒是皮肤科最常见的病理现象，对人们的精神健康和社会生活有重大影响。瞬时受体电位香草酸 3（TRPV3）通道是治疗瘙痒的一个很有前途的靶点。然而，目前报道的选择性和高效的拮抗剂较少。本研究旨在鉴定选择性 TRPV3 拮抗剂并阐明其抗瘙痒药理学。
使用 FlexStation 和钙荧光成像技术来追踪功能化合物。全细胞膜片钳技术用于记录与瘙痒相关的离子通道电流。同源重组和定点突变用于构建 TRPV3 通道嵌合体和点突变以探索药理学机制。使用小鼠模型进行体内抗瘙痒测定。
从单叶崖爬藤中分离和鉴定出一种吖啶酮生物碱（柑橘宁-II）。它直接与 TRPV3 的 S4 螺旋中的 Y564 相互作用，选择性地抑制该通道，半数最大抑制浓度（IC ）为 12.43 μM。柑橘宁-II 显示出潜在的疗效，可减轻慢性和急性瘙痒。皮内给予柑橘宁-II（143ng/皮肤部位）几乎完全抑制瘙痒行为。它还具有显著的镇痛作用。该化合物的副作用很小。
作为 TRPV3 通道的选择性和高效抑制剂，柑橘宁-II 在瘙痒动物模型中显示出有价值的治疗效果，是开发抗瘙痒药物的有前途的候选药物和/或先导分子。
