title: Fungal Glycolipid Hydrolase Inhibitors and Their Effect on Cryptococcus neoformans.
abstract: Pathogenic fungi kill an estimated 1.3 million people each year. This number is predicted to rise as drug resistance spreads, thus antifungal drugs with novel modes of action are urgently required. Fungal endoglycoceramidase-related proteins 1 and 2 (EGCrP-1 and -2), which hydrolyse glucosylceramide and ergosteryl β-glucoside, respectively, are important for fungal cell growth and have been identified as potential targets for drug development. A library of iminosugar derivatives was screened against EGCrP-1 and -2, and a number of competitive inhibitors with nanomolar affinities were identified. In addition, a mechanism-based inhibitor was shown to form a covalent derivative with EGCrP-2. Nine of the inhibitors were evaluated against Cryptococcus neoformans. Several showed growth inhibitory activity, but only against a C. neoformans strain lacking the outer fungal polysaccharide capsule; this implies that penetration into the cell is a significant handicap for these inhibitors. Pro-drug versions of these inhibitors could address this issue.
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.
authors.forename: Andres G
authors.initials: AG
authors.lastname: Santana
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.|Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Tysoe
authors.affiliation: Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.|Department of Microbiology and Immunology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Guanggan
authors.initials: G
authors.lastname: Hu
authors.affiliation: Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.|Department of Microbiology and Immunology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Kronstad
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.|Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Goddard-Borger
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.|Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
mesh_terms: D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012233:Rhizopus / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D011355:Prodrugs; D006026:Glycoside Hydrolases; C050427:endoglycoceramidase
keywords: Cryptococcus neoformans; antimycotic agents; glucosylceramide; glycosidase inhibitors; iminosugars