Cryptococcus neoformans is a fungal pathogen whose infections cause upward of 600,000 deaths per year and can be fatal for immunocompromised patients. Despite its serious problem to public health, there are currently no available vaccines and standard treatments which do not show severe side effects or not have significant fungicidal activity in the clinics. An enzyme of C. neoformans, sterylglucosidase 1 (Sgl1), cleaves sterylglucosides (SGs) into their respective sugars and steroids. Knockout of Sgl1 in mice results in the accumulation of endogenous SG, ergosterol β-D-glucoside (erg-glc), leading to the toxicity of C. neoformans (Cn). Virulence studies showed that upon inhalation of Cn Dsgl1, 100% of mice were still alive after 3 months of observation. More importantly, Δsgl1 never gains access to the brain, where the WT causes a lethal meningo-encephalitis. Thus, Sgl1 emerged as a novel and highly promising target for antifungal discovery. A high-throughput screen of 50,000 compounds identified 15 hit compounds and three of them showed effective accumulation SGs. Then, we succeeded in solving the co-crystal structure of ‘Hit9’ with Sgl1 (PDB IDs: 7LPQ, 2.32 Å), providing a basis for structure-based drug design. The computer-aided drug design (CADD) of ‘Hit9’ analogs led to a series of novel Y-shaped compounds, using Autodock 4.2 and DOCK6.9 programs. Among ca. 80 Y-shaped analogs designed and docked, SS-103 was selected for synthesis and biochemical evaluations. SS-103 showed slightly lower enzyme inhibitory activity than ‘Hit 9’ using erg-glc as the substrate. However, SS-103 exhibited substantially better efficacy than ‘Hit 9’ in the SG accumulation assay in Cn WT cells. Based on the encouraging result, the design, synthesis and biological evaluations of SS-103 analogs with excellent docking scores is ongoing. The update of the ongoing study, SAR, and pharmacological properties of lead compounds will be discussed.

Computer-aided design and of inhibitors targeting sterylglucosidase 1 (Sgl1) as next-generation antifungal agents

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