Secreted aspartic protease 2 (SAP2), a kind of virulence factor, is an emerging new antifungal target. Using docking-based virtual screening and structure-based inhibitor design, a series of novel SAP2 inhibitors were successfully identified. Among them, indolone derivative 24a showed potent SAP2 inhibitory activity (IC₅₀ = 0.92 μM). It blocked fungi biofilm and hypha formation by down-regulating the expression of genes SAP2, ECE1, ALS3 and EFG1. As a virulence factor inhibitor, compound 24a was inactive in vitro and showed potent in vivo efficacy in a murine model of invasive candidiasis. It represents a promising lead compound for the discovery of novel antifungal agents.

分泌的天冬氨酸蛋白酶2（SAP2）是一种毒性因子，是一种新兴的抗真菌靶标。使用基于对接的虚拟筛选和基于结构的抑制剂设计，成功鉴定了一系列新型SAP2抑制剂。其中，吲哚酮衍生物24a显示出有效的SAP2抑制活性（IC ₅₀ = 0.92μM）。它通过下调SAP2，ECE1，ALS3和EFG1基因的表达来阻止真菌生物膜和菌丝的形成。作为毒力因子抑制剂，化合物24a在体外侵袭性念珠菌病的鼠模型中显示出强效的体内活性。它代表了发现新型抗真菌剂的有前途的先导化合物。