Cryptococcus neoformans is a fungal pathogen whose infections cause upward of 600k deaths per year and is especially dangerous for immunocompromised patients. Despite its serious problem to public health and tremendous amount of research, there are currently no vaccines existing in the clinic and common treatments available either have harsh side effects or lack fungicidal activity. Sterylglucosidase 1 (Sgl1) is an enzyme of C. neoformans which cleaves sterylglucosides (SGs) into their respective sugars and steroids. Knockout of Sgl1 results in the accumulation of an endogenous SG, Ergosterol β-D-glucoside (erg-glc), leading to avirulence of C. neoformans in mice. A high-throughput screen of 50k compounds has identified fifteen hit compounds that inhibit Sgl1 and which three have shown to effectively accumulate SGs in vitro. These hit compounds have been re-synthesized for further biological validation and two of those compounds were successfully used to solve co-crystal structures (PDB IDs: 7LPQ, 2.32 Å, hit 9; 7LPP, 2.85 Å, hit 1) with Sgl1 allowing for an excellent model for receptor based computational drug design. Hit compounds containing a prolinol anchor, mimicking the interactions of glucose in Sgl1, show a more sensitive dose response to erg-glc hydrolysis. Computer-aided rational design based on this fragment has revealed high-scoring chemical structures which are accommodated in a Y-shaped, hydrophobic binding site. Docking calculations on designed compounds demonstrate the conserved binding mode of the glucose mimic, as well as the affinity of non-polar tail groups for auxiliary residues adjacent to the glucose binding pocket. Trends between docking scores and selected pharmacokinetic properties of these new antifungal candidates as well as their prioritization to synthesis for future biological validation will be discussed.

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

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.