Deciphering structural bases of TRP channel inhibition as foundations for the design of new drugs

破译 TRP 通道抑制的结构基础作为新药设计的基础

• 批准号: 464295817
• 负责人: Dr. Arthur Neuberger
• 金额: --
• 依托单位: Department of Biochemistry and Molecular Biophysics
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/464295817?language=en
• 关键词: Deciphering; structural; bases; TRP; channel

Any physical or mental activity involves ion channels. Ion channels are also associated with numerous human diseases, including those caused by mutations (channelopathies). Many drugs, including local anaesthetics, antianxiety agents and sedatives, target ion channels. However, highly efficient and selective drugs are missing for many ion channels due to our limited knowledge about their molecular mechanisms of regulation. I am particular interested in transient receptor potential (TRP) vanilloid subfamily (TRPV) channels. These polymodal sensory transducers respond to chemicals, temperature, mechanical stress and membrane voltage and are involved in vision, taste, olfaction, hearing, touch, thermal perception and nociception. In my proposed research project, I focus on two (patho-)physiologically important members of this family, TRPV3 and TRPV6. The calcium-selective channel TRPV6 plays a central role in calcium uptake in epithelial tissues. A classified oncochannel, TRPV6 is overexpressed in various types of human cancer cells, including breast, prostate, colon, ovarian, thyroid, endometrial, and leukaemia cancer cells. It appears that the central role of TRPV6 in cancer is to impair Ca2+ homeostasis by stimulating Ca2+ entry into the cell. Correspondingly, inhibitors of TRPV6-mediated calcium uptake are urgently needed for the treatment of TRPV6-rich tumours. I also study the thermo-sensitive channel TRPV3 which is activated by heat and several natural compounds like camphor, thymol, carvacrol, eugenol, and cannabinol. TRPV3 is predominantly expressed in skin keratinocytes and implicated in cutaneous sensation, including thermo-sensation, nociception and itch, in addition to maintenance of the skin barrier, wound healing, and hair growth. The dysfunction of TRPV3 channels, often a result of genetic mutations, is associated with numerous human skin diseases including a genodermatosis known as Olmsted syndrome, atopic dermatitis, and rosacea. Furthermore, overexpression of TRPV3 is implicated in the development and progression of colorectal and lung cancer. I aim to solve structures of TRPV3 and TRPV6 in complex with different agonists, antagonists, allosteric modulators, and ion channel blockers. Identified binding sites will be tested by site-directed mutagenesis and functional recordings. Molecular models derived from the combined structural and functional approaches will serve as templates for the design of more selective and efficacious drugs targeting inflammatory skin conditions, itch, pain, and cancer.

任何身体或精神活动都涉及离子通道。离子通道还与许多人类疾病有关，包括由突变引起的疾病（通道病）。许多药物，包括局部麻醉剂、抗焦虑剂和镇静剂，都针对离子通道。然而，由于我们对其分子调节机制的了解有限，许多离子通道缺乏高效和选择性的药物。我对瞬时受体电位 (TRP) 香草酸亚家族 (TRPV) 通道特别感兴趣。这些多模态感觉传感器对化学物质、温度、机械应力和膜电压做出反应，并涉及视觉、味觉、嗅觉、听觉、触觉、热感知和伤害感受。在我提出的研究项目中，我重点关注该家族的两个（病理）生理学重要成员：TRPV3 和 TRPV6。钙选择性通道 TRPV6 在上皮组织钙吸收中发挥核心作用。 TRPV6 是一种分类的癌通道，在多种类型的人类癌细胞中过度表达，包括乳腺癌、前列腺癌、结肠癌、卵巢癌、甲状腺癌、子宫内膜癌和白血病细胞。 TRPV6 在癌症中的核心作用似乎是通过刺激 Ca2+ 进入细胞来损害 Ca2+ 稳态。相应地，迫切需要 TRPV6 介导的钙摄取抑制剂来治疗富含 TRPV6 的肿瘤。我还研究了热敏通道 TRPV3，它被热和几种天然化合物（如樟脑、百里酚、香芹酚、丁子香酚和大麻酚）激活。 TRPV3 主要在皮肤角质形成细胞中表达，除了维持皮肤屏障、伤口愈合和毛发生长之外，还与皮肤感觉有关，包括热感觉、伤害感受和瘙痒。 TRPV3 通道的功能障碍通常是基因突变的结果，与许多人类皮肤病有关，包括称为奥姆斯特德综合征的遗传性皮肤病、特应性皮炎和红斑痤疮。此外，TRPV3的过度表达与结直肠癌和肺癌的发生和进展有关。我的目标是解析 TRPV3 和 TRPV6 与不同激动剂、拮抗剂、变构调节剂和离子通道阻滞剂的复合物结构。确定的结合位点将通过定点诱变和功能记录进行测试。由结构和功能相结合的方法衍生的分子模型将作为模板，用于设计针对炎症性皮肤病、瘙痒、疼痛和癌症的更具选择性和更有效的药物。