为克服现有抗真菌药物疗效有限、毒性大、耐药严重等问题，临床上迫切需要研发全新作用机制的抗真菌新药。以真菌毒力因子为靶标研发抗真菌药物有望能够克服耐药性和降低毒性，是本领域的前沿研究方向。毒力因子2型分泌型天冬氨酸蛋白酶（SAP2）是一个潜在的抗真菌药靶，但是目前还没有小分子抑制剂报道，因而无法进行靶点及其抑制剂的成药性验证。本课题前期研究首次获得了SAP2小分子抑制剂，并初步证实其体内抗真菌活性优秀、选择性高、毒性低。但是，先导化合物的SAP2抑制活性还有待于进一步提升，它们的体内抗真菌药效特点（预防/单独治疗/联合治疗）尚未阐明。因此，本课题拟开展基于SAP2结构的合理药物设计，获得具有nM级活性的特异性小分子抑制剂，重点阐明其构效关系、作用模式和体内抗真菌药效特点，在此基础上获得抗真菌新化学实体或者候选药物，为验证靶标提供科学依据，为研发基于新机制和新靶点的抗真菌原始创新药物奠定基础。

In order to overcome the drawbacks of current antifungal agents such as limited efficacy, significant toxicity and severe drug resistance, it is highly desirable to develop new generation of antifungal agents with new mode of action. Discovery of novel antifungal agents targeting virulence factors represents a cutting-edge area and virulence factor inhibitors have the advantages of reducing drug resistance and toxicity. Secreted aspartic protease 2 (SAP2) is a type of fungal virulence factor and has shown the potential to be an antifungal drug target. However, no small molecule SAP2 inhibitors have been reported up to date and thus the druggability of SAP2 and its inhibitors cannot be validated. In our previous studies, first-in-class small molecule SAP2 inhibitors were successfully identified, which showed good in vivo antifungal potency, good selectivity and low toxicity. However, their SAP2 inhibitory activity remains to be further improved and the feature of their in vivo antifungal activity needs to be systemically investigated. Inspired by these results, this project aims to discover specific small molecule SAP2 inhibitors with nanomolar potency by structuture-based rational drug design. In particular, structure-activity relationships, binding mode and in vivo antifungal features of the inhibitors will be clarified. As a result, this project will obtain antifungal NCEs of antifungal candidate drugs and provide scientific basis for validation of SAP2 as an antifungal target and the development of novel antifungal agents with new mode of action.