以Kv1.3离子通道为靶点的大戟属植物抗银屑病药效物质基础研究

Psoriasis, seriously affecting physical and mental health of human beings, is an autoimmune disorder disease, and Kv1.3 has become an important target for the development of anti-psoriasis drugs. Inspired by the folkloric usage of Euphorbia plants as the treatment of psoriasis , we took E. peplus and E. helioscopia as the subject and found that some diterpenoids isolated from the title plants displaying remarkable inhibitory effects on the Kv1.3 ion channel. Based on the above findings, this project wants to have a further study on the chemical constituents of another three Euphorbia species, including E. humifusa, E. lathyris, E. hylonoma, with well-documented anti-psoriasis effects and abundant resources, by taking in vitro and in vivo bioactivity evaluation model with high expression of Kv1.3 ion channel, SAR analysis and structural modification, to find potential anti-psoriasis lead compound; meanwhile, this project wants to clarify the resource quality of anti-psoriasis Euphorbia species through comparing content differences of the pharmacodynamic-characteristic peaks in LC-MS fingerprints. The implementation of this project will clarify pharmacodynamic material basis for the genus Euphorbia with anti-psoriasis activity, and also, establish a foundation for the development of anti-psoriasis drug from this genus.

银屑病，俗称牛皮癣，是严重影响人类身心健康的自身免疫性疾病，Kv1.3离子通道是该病药物研发的重要靶点。受大戟属植物抗银屑病传统药用的启发，申请人前期从该属南欧大戟和泽漆中发现一些具有显著抑制Kv1.3离子通道活性的二萜类成分。据此，本项目拟选择同属有抗银屑病记载且资源丰富的地锦草、续随子、湖北大戟等3种药用植物继续研究，通过植物化学手段对其活性部位的化学成分进行分离鉴定，结合高表达Kv1.3离子通道体内外活性评价模型、构效关系分析和结构改造，发现先导化合物；同时通过LC-MS指纹图谱中药效特征峰的比对和含量差异，阐明该属植物抗银屑病的资源品质特征。本课题的实施将明确大戟属植物抗银屑病的药效物质，为其抗银屑病药物的开发奠定基础

本项目对大戟属四种植物以及含有类似功效、类似成分的近源植物中的萜类物质开展化学成分及其靶向Kv1.3离子通道的抗银屑病活性研究，共分离到萜类成分184个，结构类型多样，骨架涉及多种二萜、三萜以及倍半萜，其中新化合物102个，包括新颖的9(10→11)-abeo-10,12-cyclojatrophane型二萜、基于jatrophane骨架的新颖螺环内酯二萜、罕见的bicyclo[8.3.0]tridecane骨架的jatrophane二萜以及基于lanostane骨架含有罕见的spiro[4.5]decan-6-one结构片段的三萜等。对分离到的代表性单体化合物在高表达Kv1.3离子通道细胞模型中进行活性评价，发现大环二萜类，特别是jatrophane型，展示出明显优于阳性药paroxetime的抑制活性，这些发现初步阐明可以靶向Kv1.3离子通道的抗银屑病大戟属药用植物在化学成分上的资源特征。同时基于初步的构效关系分析，对含量丰富的jatrophane型化合物开展结构改造，发现jatrophane型结构中的双键并非抑制活性所必需，并通过ODPM重排反应成功验证新骨架euphohelioscoid A的生源推导途径，为今后基于该类优势结构骨架的Kv1.3离子通道抑制剂的深入合成研究提供参考。在咪喹莫特诱导的银屑病小鼠模型中，药效学评价表明jatrophane型大量成分euphornin D可显著改善银屑病小鼠皮肤表观的发炎、皮屑等病变症状，降低模型小鼠的表皮层厚度，深入的药理机制研究还发现该化合物可显著改善血清中CD3+CD4+ T淋巴细胞和CD44+CD62+ T淋巴细胞的分化，并下调血清中IL-12、IL-17、IL-22、TNF-α等相关炎症因子的mRNA转录水平，说明大戟属植物中诸如euphornin D这类jatrophane型二萜成分可作为靶向Kv1.3离子通道抗银屑病先导化合物进行下一步成药性研究。