Targeting fungal virulence factor by small molecules: Structure-based discovery of novel secreted aspartic protease 2 (SAP2) inhibitors

• Published in: European journal of medicinal chemistry 2020-09, Vol.201, p.112515-112515, Article 112515
• Main Authors: Li, Chenglan, Liu, Yang, Wu, Shanchao, Han, Guiyan, Tu, Jie, Dong, Guoqiang, Liu, Na, Sheng, Chunquan
• Format: Article
• Language: English
• Subjects: Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - metabolism; Antifungal Agents - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Biofilms - drug effects; Candida albicans - drug effects; Candida albicans - physiology; Candida tropicalis - drug effects; Candida tropicalis - physiology; Catalytic Domain; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - chemistry; Fungal Proteins - metabolism; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Oxindoles - chemical synthesis; Oxindoles - metabolism; Oxindoles - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; Protein Binding; Pyrazolones - chemical synthesis; Pyrazolones - metabolism; Pyrazolones - pharmacology; Secreted aspartic protease 2; Structure-Activity Relationship; Virulence factor; Virulence Factors - antagonists & inhibitors; Virulence Factors - chemistry; Virulence Factors - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112515

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. [Display omitted] •A series of novel SAP2 inhibitors were successfully identified by virtual screening and hit optimization.•Indolone inhibitor 24a showed potent SAP2 inhibitory activity and blocked fungi biofilm and hypha formation.•Compound 24a showed potent in vivo efficacy in a murine model of invasive candidiasis.