TLR7激动剂治疗化疗脱发的机制及药理活性研究

Hair loss is both the common dermatosis and side-effect in cancer chemotherapeutic patients. Whether the hair could revive depends on hair follicles’ damage extent. However, there is no any effective drugs to treat chemotherapy-induced alopecia. TLR7 has a special distribution advantage in hair follicles, and expresses with hair follicle stem cells. TLR7 agonists induce hair follicle stem cells proliferation and differentiation into hair follicles via several signaling pathways. Imiquimod is recognized as the TLR7 agonist. Our team synthesized a series of compounds based on drug design and structure transformation avoiding patents, and found hair follicle number in mouse back increased greatly using one of the compounds in mouse HE test. This project will confirm its TLR7 agonist activity and hair follicle stem cell proliferation in molecular mechanism, test its activity on hair follicle stem cell in vitro. And then test its treatment effect in mouse chemotherapy-induced alopecia model and mouse breast cancer treatment model. This project designed ointment is local external drug, thereof its safety can be easily controlled, and it is limited to act locally in human body, so that it scarcely influences cancer treatment. This project aims at confirm the new compound’s comprehensive pharmacological activity to lay the preclinical studies for drug development for chemotherapy-induced alopecia.

脱发是一种常见的皮肤病也是肿瘤化疗患者常见的副作用。头发能否再生取决于毛囊受破坏的程度。目前尚无有效药物对化疗脱发进行治疗。TLR7 在毛囊中有特殊的分布优势，与毛囊干细胞存在共表达，TLR7激动剂能通过多条信号通路诱导毛囊干细胞增殖并分化为毛囊。咪喹莫特是公认的TLR7激动剂。本课题组前期进行药物设计和结构改造，避开了专利保护，合成了一系列化合物；通过HE染色观察到，在其中一个新化合物作用下，小鼠皮肤毛囊数量有显著增加。本项目将对其TLR7激动活性和毛囊干细胞增殖活性进行分子机制验证，在体外考察对毛囊干细胞的作用，然后在小鼠化疗脱毛模型和小鼠乳腺癌治疗模型上讨论此化合物的治疗效果。本项目设计的乳膏剂为局部外用药物，药品本身安全性容易掌控、作用范围上对机体整体影响小，因此对化疗治疗几乎无影响。本项目旨在对此全新化合物进行全面的药理活性确证，为治疗化疗脱发新药开发奠定临床前药理基础。

脱发是肿瘤化疗患者常见的副作用。目前对化疗脱发的治疗还没有特效药，市面存在的治疗方式除了作用有限的“冰帽”外，其他治疗方式未得到临床证实，或难以满足临床需求。本项目合成了全新喹啉类化合物，考察了水溶性较好的化合物在酶水平的作用机制、细胞水平对毛囊干细胞增殖活性、动物化疗实验和乳腺癌小鼠治疗实验中对毛囊数量的促进作用。酶水平研究发现合成的新化合物6b对毛囊干细胞的促进机制不是通过TLR7激动机理完成，其毛囊干细胞增殖主要机理还需要进一步探讨。新化合物及其乳膏剂对小鼠毛囊的增殖促进作用为治疗化疗脱发新药开发奠定了临床前药理基础。为丰富TLR7激动剂结构，本研究通过基于受体 (TLR7 PDB code: 5GMH)计算机辅助药物设计，设计了432个化合物，根据打分结果、是否含有糖基、合成路线可行性进行人工二次筛选。再将筛选所得的27个化合物进行TLR7激动活性的酶水平实验和NO抑制实验测试。有趣的是，其中有5个化合物竟然表现出TLR7抑制活性。此次通过设计激动剂方案得到的抑制剂化合物为抑制剂/激动剂与蛋白受体相互作用位点探讨和开发新型小分子药物提供了底物基础。