Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans - In Silico, In Vitro and In Vivo Approaches.

Andre Santos, Lys Braga-Silva, Diego Gonçalves, Livia S. Ramos, Simone Oliveira, Lucieri Souza, Vanessa Oliveira, Roberto Lins, Marcia Pinto, Julian Esteban Munoz Henao, Carlos Taborda, Marta Branquinha

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

11 Citas (Scopus)

Resumen

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 obviouslymain target of lopinavir. To confirmthis 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 M). 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.
Idioma originalInglés
Páginas (desde-hasta)1-33
Número de páginas33
PublicaciónJournal of Fungi
Volumen7
N.º424
DOI
EstadoPublicada - may. 28 2021

Citar esto