Antifungal agent 151

Antifungalagent 151 is an inhibitor of Prp8 intein, blocking its self-splicing and thus preventing the maturation of Prp8 protein. It exhibits in vitro antifungal activity against Cryptococcus neoformans and Cryptococcus gattii. Antifungalagent 151 is applicable in research related to cryptococcal pneumonia.

Antifungal agent 151 (compound B5) exhibits potent inhibition against Cryptococcus neoformans H99, Cryptococcus gattii R265, fluconazole-resistant Cryptococcus neoformans (strain 313), and clinical isolates with a MIC range of 0.5 to 2 μg/mL. At 8.0 μg/mL, it demonstrates rapid, concentration-dependent fungicidal activity against C. neoformans H99, eradicating fungi within two hours. At 2.0 μg/mL, it induces transcriptional reprogramming in C. neoformans H99, inhibits normal intron splicing, and alters oxidative stress, DNA damage response, and metabolic gene expression. The compound binds to the Prp8 intron-active site through hydrogen bonds and favorable interactions with Cys1 [1]. The IC50 values are 14.99 μg/mL for LO2 cells and 10.31 μg/mL for A549 cells. Its lower MIC against C. neoformans results in a therapeutic index higher than 6G-318S. At a concentration of 64 μg/mL, it shows good blood compatibility with a hemolysis rate of only 3.2%.

Compound B5, also known as antifungal agent 151, administered intraperitoneally at a dosage of 10 mg/kg daily for 7 consecutive days, effectively reduces fungal burden and pathological damage in a mouse model of Cryptococcus neoformans pneumonia, while also demonstrating good biosafety.