Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases.
Shuvechha ChakrabortyKshitija RahateChandan KumarSusan Idicula-ThomasPublished in: Drug development research (2022)
For widening the therapeutic options for Candida management, the druggability of Candida proteome was systematically investigated using an innovative pipeline of high-throughput data mining algorithms, followed by in vitro validation of the observations. Through this exercise, HIV-1 protease was found to share structural similarity with secreted aspartyl protease-3 (SAP3), a virulence protein of Candida. Using the molecular fingerprint of HIV-1 protease inhibitor GRL-09510, we performed virtual screening of peptidomimetic library followed by high-precision docking and MD simulations for discovery of SAP inhibitors. Wet-lab validation of the four shortlisted peptidomimetics revealed that two molecules, when used in combination with fluconazole, could significantly reduce the dosage of fluconazole required for 50% inhibition of Candida albicans. The SAP inhibitory activity of these peptidomimetics was confirmed through SAP assays and found to be on par with pepstatin A, a known peptidomimetic inhibitor of aspartyl proteases.
Keyphrases
- candida albicans
- biofilm formation
- high throughput
- antiretroviral therapy
- molecular dynamics
- hiv positive
- hiv infected
- human immunodeficiency virus
- hiv testing
- hepatitis c virus
- single cell
- hiv aids
- escherichia coli
- small molecule
- men who have sex with men
- pseudomonas aeruginosa
- staphylococcus aureus
- high intensity
- physical activity
- molecular dynamics simulations
- electronic health record
- cystic fibrosis
- mass spectrometry
- antimicrobial resistance
- high speed