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

  • Eur J Med Chem. 2020 Sep 1;201:112515. doi: 10.1016/j.ejmech.2020.112515.
Chenglan Li  1 ,  Yang Liu  2 ,  Shanchao Wu  3 ,  Guiyan Han  3 ,  Jie Tu  3 ,  Guoqiang Dong  4 ,  Na Liu  5 ,  Chunquan Sheng  6
Affiliations
  • 1. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 2. Department of Pharmacy, No. 971 Hospital of PLA, Qingdao, 266071, China.
  • 3. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 4. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
  • 5. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
  • 6. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 32623209 DOI: 10.1016/j.ejmech.2020.112515
Abstract

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.

Keywords
Antifungal; Secreted aspartic protease 2; Virulence factor.
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