title: Bicyclic peptidomimetics targeting secreted aspartic protease 2 (SAP2) from Candida albicans reveal a constrained inhibitory chemotype.
abstract: The in vitro screening of stereoisomeric bicyclic peptidomimetics towards SAP2 of Candida albicans revealed a constrained chemotype as aspartic protease inhibitor in the micromolar to nanomolar range. The results indicated that the acetal bridge may serve as a transition-state isostere, and that the right match between interactions with subsites and the orientation by hydrogen bonding with Gly85 is the main requisite for inhibitory activity. Molecular docking calculations suggested the bicyclic acetal scaffold to be capable of interacting with the two catalytic aspartic acids, thus resulting in good inhibitory activity with only two hydrophobic groups addressing the enzyme catalytic subsites.
authors.affiliation: Department of Chemistry Ugo Schiff, University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Calugi
authors.forename: Andrea
authors.initials: A
authors.lastname: Trabocchi
authors.forename: Flavia
authors.initials: F
authors.lastname: De Bernardis
authors.forename: Silvia
authors.initials: S
authors.lastname: Arancia
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Navarra
authors.forename: Roberto
authors.initials: R
authors.lastname: Cauda
authors.forename: Antonio
authors.initials: A
authors.lastname: Cassone
authors.forename: Antonio
authors.initials: A
authors.lastname: Guarna
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D016282:Aspartic Acid Endopeptidases; C090753:SAP2 protein, Candida