2. Academic Validation
  3. Design, synthesis, and antifungal evaluation of Prp8 Intein-targeting small molecule inhibitors against Cryptococcus neoformans

Design, synthesis, and antifungal evaluation of Prp8 Intein-targeting small molecule inhibitors against Cryptococcus neoformans

  • Bioorg Chem. 2026 Mar:170:109490. doi: 10.1016/j.bioorg.2026.109490.
Ying Tao 1,  Lin Wang 1,  Xingsheng Huang 1,  Fang Wen 1,  Xiaoqin Tan 1,  Yiyun Zhu 1,  Jianhan Sun 2,  Xinyan Wan 3,  Xiuyun Tian 4,  Ting Guo 5,  Wei Zhou 6,  Guojian Liao 7
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
  • 2 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; National Demonstration Center for Experimental Pharmacy Education (Southwest University), Chongqing, China.
  • 3 College of Pharmaceutical Sciences, Chongqing Medical University, Chongqing 400715, China.
  • 4 State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
  • 6 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
  • 7 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
PMID: 41539041 DOI: 10.1016/j.bioorg.2026.109490
Abstract

Cryptococcus neoformans, classified as a critical priority pathogen among fungi, highlights the urgent need for safe and effective novel Antifungal drugs. The unique intein self-splicing process of the Prp8 protein in pathogenic fungi makes the Prp8 intein an attractive Antifungal target. Taking the Prp8 intein inhibitor 6G-318S as a lead compound, a series of 1,2,3-thiadiazole derivatives were designed and synthesized. Among these, compound B5 exhibited excellent in vitro Antifungal activity against C. neoformans (MIC = 1.0 μg/mL) and C. gattii (MIC = 0.5 μg/mL). Notably, B5 exhibited a 57-fold increase in aqueous solubility relative to 6G-318S, along with exceptional in vivo Antifungal efficacy and favorable safety in animal models. Collectively, these results highlight compound B5 as a promising candidate for the development of Prp8 intein-targeting inhibitors as novel Antifungal agents.

Keywords

Antifungal; Cryptococcus neoformans; Prp8 intein; Structural optimization.

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