血红蛋白衍生肽介导的抗隐球菌病药物递送研究

隐球菌病是指由新生隐球菌及其变种引发的体内深部真菌感染，危害大且预后差。该病存在的多重生物学屏障显著限制抗菌药物发挥疗效：①病菌具有荚膜②病菌能寄生于宿主巨噬细胞内③病菌所侵袭的中枢神经系统存在血-脑屏障。我们前期实验发现，经血红蛋白偶联的载体能识别隐球菌并能靶向脑、肺等感染部位，其潜在靶点是病菌分泌于胞壁、荚膜、受感染巨噬细胞表面以及受感染脏器血管内皮的血红素载体蛋白Cig1。但血红蛋白自身存在缺陷，应用受到限制。在已有工作及文献调研基础上，项目拟探索一种针对隐球菌病的靶向递药新策略：基于血红蛋白适宜亚基设计含血红素单元的多肽导向分子，该多肽能识别Cig1并可经优化获得较好穿膜能力；进一步构建多肽修饰的载药脂质体，所得制剂能有效克服多重屏障并靶向清除胞内/外感染。项目注重递药系统成药性，提出以感染微环境中胞外分泌蛋白作为病程多环节共有靶点的递药新模式，有望实现“简单”制剂强效对抗复杂感染

Cryptococcosis is the deep fungal infection in the body caused by Cryptococcus neoformans and its variants, with poor prognosis and serious threats to human health. The multiple biological barriers towards the infection significantly limit the effectiveness of antifungal drugs: ① the fungi have capsules ② the fungi can hide inside the host macrophage ③ the central nervous system, as the target of the fungi, is protected by the blood-brain barrier. According to our previous researches, the hemoglobin-conjugated delivery systems has the ability to not only recognize Cryptococcus, but also target the infection sites such as brain, lung, etc., and the potential target is the hemophore Cig1 protein secreted by the fungi, which is distributed on the cell wall, capsule, the surface of infected macrophages and the vascular endothelium in infected organs. However, the defects of the hemoglobin posed limitations to its further application. Based on the existing work and literature research, the project aims to explore a new strategy for the targeted drug delivery against cryptococcosis. Firstly, the project plans to design the targeting peptide containing a heme unit based on the appropriate subunit of hemoglobin, which is expected to recognize Cig1, and could be optimized to guarantee efficient membrane penetration. Then the peptide-modified, drug-loaded liposomes would be further constructed, and the resulting formulation is expected to effectively overcome multiple barriers and targetedly clear the extracellular/intracellular infections. The project pays attention to the druggability of the delivery system, and proposes a new model for drug delivery aiming at the extracellular secretory protein in the infection microenvironment as the common target shared by multiple links in the course of the disease. It is expected to achieve effective therapy against complex infections using a "simple" formulation.