新的抗真菌药物靶点研究进展

近30年来,侵袭性真菌感染发病率持续上升,病死率居高不下,而治疗药物十分有限是造成其高致死率的重要因素之一。因此,发现新的抗真菌靶点和药物,已成为迫切需要。正在研究的新的抗真菌靶点如下：一是信号通路介导的抗真菌靶点,包括钙调神经磷酸酶及其分子伴侣Hsp90、3-磷酸肌醇依赖性蛋白激酶（PKH）以及参与Ras蛋白修饰的相关酶等,其拮抗剂包括传统免疫抑制剂的类似物以及Hsp90抗体、KP-372-1和PS77以及手霉素A等;二是GPI锚定蛋白合成通路的催化酶,其抑制剂有E1210和M720等化合物;三是分泌型天冬氨酸蛋白酶,肽类、逆转录病毒抑制剂,以及砜类的衍生物等均可以抑制这一靶点;四是海藻糖的合成的两个关键酶Tps1和Tps2。鉴于侵袭性真菌感染严重影响人类公共健康安全,而新型抗真菌药物的研发又依赖于新靶点的探索,因此,本文靶向这一核心真菌临床问题,系统介绍了当前新的抗真菌药物靶点发展概况,并在靶点选择可行性以及针对靶点的药物研发策略上提出见解。

The research progress of novel antifungal drug targets

In the past three decades, the incidence of invasive fungal infections has continued to rise, and the mortality rate remains high. The limited therapeutic drugs are one of the important factors that contribute to its high mortality rate. The discovery of new targets and new antifungal drugs has become an urgent need. The new antifungal targets under development can be summed up as following aspects: (1) Signal pathway-mediated antifungal targets, including calcineurin and its molecular chaperone Hsp90, 3-phosphoinositide-dependent protein kinase (PKH), and the enzymes that modify Ras protein, etc. Their antagonists include analogues of traditional immunosuppressants and antibodies to Hsp90, KP-372-1 and PS77, and leucomycin A etc; (2) The catalytic enzymes of GPI-anchored protein synthesis pathways. Their inhibitors include E1210 and M720; (3) Secreted aspartic proteases which can be inhibeted by special peptides, retrovirus inhibitors, and sulfone derivatives; (4) The two key enzymes, Tps1 and Tps2, of the trehalose synthesis. In consideration of invasive fungal infections seriously affect public health, and the development of new antifungal drugs relies on the exploration of new targets, therefore, this review aims at this core clinical problem and systematically introduces the current development of new antifungal drug targets, and provides the views on the feasibility of target selection and drug development strategies.