基于Pdr1-KIX蛋白-蛋白相互作用的抗真菌先导物设计、合成和生物活性研究

深部真菌感染的致死率日趋升高，真菌耐药问题愈发严重，但现有抗真菌药物存在种类少、毒性大、抗菌谱窄等弊端，亟待研发全新干预靶点和全新分子骨架的抗真菌原创药物。Pdr1-KIX蛋白-蛋白相互作用是极具潜力的抗真菌新靶点，但由于缺乏高活性的抑制剂，难以深入阐明靶点的生物功能和可药性。本课题前期设计得到了结构新颖、活性强，体内外抗真菌药效好的KIX小分子抑制剂，并首次发现将Pdr1-KIX阻断后兼具直接抗真菌活性和协同抗耐药功能。在此基础上，本项目以Pdr1-KIX相互作用的“可药性”及其抑制剂的“成药性”为科学问题，深入开展新型抑制剂的合理设计、抗真菌活性和作用机制研究，发现高活性抑制剂并阐明其抗真菌药效特点，为研发全新作用机制的抗真菌候选药物奠定基础。

The mortality of invasive fungal infection is increasing rapidly, and severe drug resistance has been emerged. However, clinically antifungal agents have several deficiencies such as limited classes, high toxicity and narrow antifungal spectrum. It is urgent to develop innovative antifungal agents with novel intervention target and molecular scaffold. Pdr1-KIX protein-protein interaction is a potential antifungal target, whose biological function and druggability is poorly illustrated due to the lack of potent inhibitors. In our previous studies, small molecule KIX inhibitors with novel chemotype, high binding affinity and good in vitro/vivo antifungal efficacy were designed. Moreover, it was identified unprecedentedly that it caused both direct antifungal activity and synergistic anti-resistance profiles by blocking Pdr1-KIX interaction. This project aims to clarify the “druggability” of Pdr1-KIX interaction and the “drug-likeness” of its inhibitors based on the above results. In particular, rational drug design of novel inhibitors, antifungal activity assay and mechanism investigation will be performed. Taken together, this project will discover potent Pdr1-KIX inhibitors and clarify their antifungal features, laying the foundation for the development of innovative antifungal drug candidates.