基于真菌毒力因子SAP2的新型抗真菌先导物发现和优化研究

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.

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。

本课题针对抗真菌新靶点SAP2，完成了新型抑制剂的分子设计、结构优化、构效关系、体内外抗真菌药效研究。设计合成得到100余个全新的SAP2抑制剂，从中优选得到2个高活性化合物，在体内模型中显示了优秀的抗真菌药效，显示了良好的成药前景。本项目研究成果的创新性在于：开辟以真菌毒力因子为靶标的抗真菌药物研究新方向，首次设计得到了SAP2小分子抑制剂，并初步阐明其抗真菌药效特点，优选得到具有优秀体内药效的成药性分子。课题研究结果为验证SAP2作为抗真菌新药靶的成药性能提供了关键科学证据，为研发抗真菌原创新药提供了成药性先导化合物和候选药物并奠定了理论基础。项目成果在Journal of Medicinal Chemistry、Chemical Communications等期刊发表标注项目资助SCI论文8篇，其中影响因子大于5分文章6篇，获得国家发明专利授权2项。本项目硕士研究生3名，博士研究生2名，其中1名获得全军优秀硕士学位论文，建立了一支具有较高研究水平的抗真菌新药研究团队。相关研究成果受邀在2019年世界顶尖科学家青年论坛上进行了交流，在全国药物化学学术会议等学术会议作邀请报告5次。