Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches
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Le résumé fourni par la source
The repurposing strategy was applied herein to evaluate the effects of lopinavir, an aspartic protease inhibitor currently used in the treatment of HIV-infected individuals, on the globally widespread opportunistic human fungal pathogen Candida albicans by using in silico, in vitro and in vivo approaches in order to decipher its targets on fungal cells and its antifungal mechanisms of action. Secreted aspartic proteases (Saps) are the obviously main target of lopinavir. To confirm this hypothesis, molecular docking assays revealed that lopinavir bound to the Sap2 catalytic site of C. albicans as well as inhibited the Sap hydrolytic activity in a typically dose-dependent manner. The inhibition of Saps culminated in the inability of C. albicans yeasts to assimilate the unique nitrogen source (albumin) available in the culture medium, culminating with fungal growth inhibition (IC50 = 39.8 µM). The antifungal action of lopinavir was corroborated by distinct microscopy analyses, which evidenced drastic and irreversible changes in the morphology that justified the fungal death. Furthermore, our results revealed that lopinavir was able to (i) arrest the yeasts-into-hyphae transformation, (ii) disturb the synthesis of neutral lipids, including ergosterol, (iii) modulate the surface-located molecules, such as Saps and mannose-, sialic acid- and N-acetylglucosamine-containing glycoconjugates, (iv) diminish the secretion of hydrolytic enzymes, such as Saps and esterase, (v) negatively influence the biofilm formation on polystyrene surface, (vi) block the in vitro adhesion to epithelial cells, (vii) contain the in vivo infection in both immunocompetent and immunosuppressed mice and (viii) reduce the Sap production by yeasts recovered from kidneys of infected animals. Conclusively, the exposed results highlight that lopinavir may be used as a promising repurposing drug against C. albicans infection as well as may be used as a lead compound for the development of novel antifungal drugs.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches
- Date Crossref
- 28/05/2021
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Universidade Federal do Rio de Janeiro Instituto de Microbiologia Paulo de Góes (IMPG) pays non établi dans la noticeUniversité ou école supérieure
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Fundação Oswaldo Cruz pays non établi dans la noticeStructure de recherche
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Universidade Federal Fluminense Instituto Biomédico pays non établi dans la noticeUniversité ou école supérieure
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Universidad del Rosario pays non établi dans la noticeUniversité ou école supérieure
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Universidade de São Paulo Instituto de Ciências Biomédicas pays non établi dans la noticeUniversité ou école supérieure
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Instituto Aggeu Magalhães pays non établi dans la noticeStructure de recherche
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School of Medicine and Health Sciences Medicine Traslacional Institute pays non établi dans la noticeUniversité ou école supérieure
Instituto de Microbiologia Paulo de Góes (IMPG) — Universidade Federal do Rio de Janeiro, Fundação Oswaldo Cruz et Instituto Biomédico — Universidade Federal Fluminense, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.