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Article

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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Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, Brazil
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Programa de Pós-Graduação em Bioquímica (PPGBq), Instituto de Química (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-909, Brazil
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Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, Recife 50740-465, Brazil
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Departamento de Microbiologia e Parasitologia, Instituto Biomédico, Universidade Federal Fluminense (UFF), Niterói 24210-130, Brazil
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MICROS Group, Medicine Traslacional Institute, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
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Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo (USP), São Paulo 05508-060, Brazil
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Laboratório de Micologia Médica—LIM53/IMTSP, Universidade de São Paulo (USP), São Paulo 05508-000, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editor: Renátó Kovács
J. Fungi 2021, 7(6), 424; https://doi.org/10.3390/jof7060424
Received: 30 April 2021 / Revised: 25 May 2021 / Accepted: 25 May 2021 / Published: 28 May 2021
(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)
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. View Full-Text
Keywords: Candida albicans; drug repurposing; HIV protease inhibitors; secreted aspartic proteases; lopinavir; virulence; adhesion; biofilm; morphogenesis; animal infection Candida albicans; drug repurposing; HIV protease inhibitors; secreted aspartic proteases; lopinavir; virulence; adhesion; biofilm; morphogenesis; animal infection
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MDPI and ACS Style

Santos, A.L.S.; Braga-Silva, L.A.; Gonçalves, D.S.; Ramos, L.S.; Oliveira, S.S.C.; Souza, L.O.P.; Oliveira, V.S.; Lins, R.D.; Pinto, M.R.; Muñoz, J.E.; Taborda, C.P.; Branquinha, M.H. Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches. J. Fungi 2021, 7, 424. https://doi.org/10.3390/jof7060424

AMA Style

Santos ALS, Braga-Silva LA, Gonçalves DS, Ramos LS, Oliveira SSC, Souza LOP, Oliveira VS, Lins RD, Pinto MR, Muñoz JE, Taborda CP, Branquinha MH. Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches. Journal of Fungi. 2021; 7(6):424. https://doi.org/10.3390/jof7060424

Chicago/Turabian Style

Santos, André L.S., Lys A. Braga-Silva, Diego S. Gonçalves, Lívia S. Ramos, Simone S.C. Oliveira, Lucieri O.P. Souza, Vanessa S. Oliveira, Roberto D. Lins, Marcia R. Pinto, Julian E. Muñoz, Carlos P. Taborda, and Marta H. Branquinha 2021. "Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches" Journal of Fungi 7, no. 6: 424. https://doi.org/10.3390/jof7060424

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