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Bicyclic peptidomimetics targeting secreted aspartic protease 2 (SAP2) from Candida albicans reveal a constrained inhibitory chemotype |
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| Authors: | Chiara Calugi Andrea Trabocchi Flavia De Bernardis Silvia Arancia Pierluigi Navarra Roberto Cauda Antonio Cassone Antonio Guarna |
| Affiliation: | 1. Department of Chemistry ‘Ugo Schiff’, University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy;2. Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;3. Department of Infectious Diseases, Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy;4. Institute of Pharmacology, Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy |
| 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. |
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