Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents
| dc.contributor.author | Pereira de Sa, Nivea | |
| dc.contributor.author | Taouil, Adam | |
| dc.contributor.author | Kim, Jinwoo | |
| dc.contributor.author | Clement, Timothy | |
| dc.contributor.author | Hoffmann, Reece M. | |
| dc.contributor.author | Burke, John E. | |
| dc.contributor.author | Rizzo, Robert C. | |
| dc.contributor.author | Ojima, Iwao | |
| dc.contributor.author | Del Poeta, Maurizio | |
| dc.contributor.author | Airola, Michael V. | |
| dc.date.accessioned | 2023-07-05T15:41:27Z | |
| dc.date.available | 2023-07-05T15:41:27Z | |
| dc.date.copyright | 2021 | en_US |
| dc.date.issued | 2021 | |
| dc.description.abstract | Pathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus Cryptococcus neoformans (Cn) results in ergosterol 3β-D-glucoside accumulation, renders Cn non-pathogenic, and immunizes mice against secondary infections by wild-type Cn, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in Cn cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the Cn Δsgl1 mutant and prevents dissemination of wild-type Cn to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1’s substrate specificity and enable the rational design of antifungal agents targeting Sgl1. | en_US |
| dc.description.reviewstatus | Reviewed | en_US |
| dc.description.scholarlevel | Faculty | en_US |
| dc.description.sponsorship | We thank the staff at the AMX and FMX (NSLS-II) and GM-CAT (APS) beamlines for assistance during data collection, Yong Mi Choi (Airola lab) for help with Sgl1 purification, and Robert Rieger and Izolda Mileva from Stony Brook Proteomics and Lipidomics facilities who provided valuable assistance for LC-MS analysis. We are also grateful to Dr. Tadashi Honda, Discovery Chemistry Laboratory, for his valuable advice on the chemical synthesis of Hits 1, 9, 15, as well as Dr. Bela Ruzsicska, Analytical Instrumentation Laboratory, for HRMS analysis at the Institute of Chemical Biology and Drug Discovery, Stony Brook University. This work was supported by a grant from the Feldstein Medical Foundation 1169048 (M.V.A.), a Stony Brook School of Medicine Fusion Award 1149556 (M.V.A. and M.D.P.), National Institutes of Health grants R35GM128666 (M.V.A.), AI136934 (M.D.P.), AI116420 (M.D.P.), AI125770 (M.D.P.), and R35GM126906 (R.C.R.), a Merit Review Grant I01BX002924 from the Veterans Affairs Program (M.D.P.), the NSERC Discovery Grant NSERC-2020-04241 (J.E.B.), and the Michael Smith Foundation for Health Research (J.E.B., Scholar Award 17686). Maurizio Del Poeta is a Burroughs Welcome Investigator in Infectious Diseases. | en_US |
| dc.identifier.citation | Pereira de Sa, N., Taouil, A., Kim, J. et al. (2021). Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents. Nat Commun 12, 5885. https://doi.org/10.1038/s41467-021-26163-5 | en_US |
| dc.identifier.uri | https://doi.org/10.1038/s41467-021-26163-5 | |
| dc.identifier.uri | http://hdl.handle.net/1828/15203 | |
| dc.language.iso | en | en_US |
| dc.publisher | Nature Communications | en_US |
| dc.subject.department | Department of Biochemistry and Microbiology | |
| dc.title | Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents | en_US |
| dc.type | Article | en_US |