Aspartic peptidase of <i>Phialophora verrucosa</i> as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction

Granato, Marcela Q.; Sousa, Ingrid S.; Rosa, Thabatta Leal Silveira Andrezo; Gonçalves, Diego de Souza; Seabra, Sérgio Henrique; Alviano, Daniela Sales; Pessolani, Maria Cristina Vidal; Santos, André Luis Souza dos; Kneipp, Lucimar F.

doi:10.1080/14756366.2020.1724994

Cited by 5 publications

(9 citation statements)

References 64 publications

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“…Mycelial [65], conidial [34] and sclerotic [66] cells of the filamentous fungus Fonsecaea pedrosoi were able to produce Saps when grown under chemically defined conditions, which were inhibited at different proportions to indinavir, saquinavir, ritonavir and nelfinavir. Phialophora verrucosa mycelial cells also extracellularly released aspartic-type protease, which was inhibited by HIV PIs at 100 µM as follows: amprenavir (~77%), ritonavir (~76%), lopinavir (~75%), indinavir (~51%), atazanavir (~46%), saquinavir (~41%) and nelfinavir (~36%) [67]. Collectively, all these results confirm that aspartic proteases produced by opportunistic human fungal pathogens are genuine targets of the HIV PIs.…”

Section: Lopinavir Inhibits Sap Activitysupporting

confidence: 52%

“…In parallel, a significant reduction in the cellular granularity was seen in HIV PIs-treated F. pedrosoi conidia, but no alteration was observed in the size parameter [41]. Ritonavir was capable of promoting significant growth inhibition of P. verrucosa, with a significant decrease of 60, 45 and 40% at 400, 200 and 100 µM, respectively, displaying an IC 50 of 141.42 µM [67].…”

Section: Lopinavir Interferes With Growth Behavior Morphometrical Par...mentioning

confidence: 89%

“…Lopinavir at 100 µM diminished the interaction process between P. verrucosa conidia and macrophages at about 50%. In addition, the combination of lopinavir (50 µM) plus ritonavir (12.5 µM) affected the adhesion index, reducing it by approximately 40% [67]. Furthermore, the killing capability of macrophages against P. verrucosa conidia was significantly enhanced in the presence of lopinavir and ritonavir, individually and in combination [67].…”

Section: Lopinavir Blocks the In Vitro Adhesion To Epithelial Cellsmentioning

confidence: 99%

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

Santos

Braga-Silva

Gonçalves

et al. 2021

JoF

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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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Section: Lopinavir Inhibits Sap Activitysupporting

confidence: 52%

Section: Lopinavir Interferes With Growth Behavior Morphometrical Par...mentioning

confidence: 89%

Section: Lopinavir Blocks the In Vitro Adhesion To Epithelial Cellsmentioning

confidence: 99%

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

Santos

Braga-Silva

Gonçalves

et al. 2021

JoF

Self Cite

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“…Lopinavir has been shown to be safe for HIV-infected children with severe acute malnutrition [ 7 ]. Lopinavir exhibited an inhibition of growth of some fungal cells and has potential effect as a therapy for fungal infections [ 8 , 9 ]. In addition, lopinavir has been investigated as a treatment plan for some parasitic infections [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Lopinavir-menthol co-crystals for enhanced dissolution rate and intestinal absorption

Fayed

Arafa

Essa

et al. 2022

Journal of Drug Delivery Science and Technology

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“…Therefore, the action of these three drugs can be complementary in the treatment of long-standing and severe cases of CBM. Other molecules, such as tricyclazole, an inhibitor of melanin [197], HIV peptidase inhibitors [198], and 1,10-phenanthroline-5,6-dione [199], have also been studied in the context of CBM and show interesting fungicidal activity.…”

Section: Treatment Of Cbmmentioning

confidence: 99%

Reviewing the Etiologic Agents, Microbe-Host Relationship, Immune Response, Diagnosis, and Treatment in Chromoblastomycosis

Passero

Cavallone

Belda

2021

Journal of Immunology Research

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Chromoblastomycosis (CBM) is a neglected human disease, caused by different species of pigmented dematiaceous fungi that cause subcutaneous infections. This disease has been considered an occupational disease, occurring among people working in the field of agriculture, particularly in low-income countries. In 1914, the first case of CBM was described in Brazil, and although efforts have been made, few scientific and technological advances have been made in this area. In the field of fungi and host cell relationship, a very reduced number of antigens were characterized, but available data suggest that ectoantigens bind to the cell membrane of host cells and modulate the phagocytic, immunological, and microbicidal responses of immune cells. Furthermore, antigens cleave extracellular proteins in tissues, allowing fungi to spread. On the contrary, if phagocytic cells are able to present antigens in MHC molecules to T lymphocytes in the presence of costimulation and IL-12, a Th1 immune response will develop and a relative control of the disease will be observed. Despite knowledge of the resistance and susceptibility in CBM, up to now, no effective vaccines have been developed. In the field of chemotherapy, most patients are treated with conventional antifungal drugs, such as itraconazole and terbinafine, but these drugs exhibit limitations, considering that not all patients heal cutaneous lesions. Few advances in treatment have been made so far, but one of the most promising ones is based on the use of immunomodulators, such as imiquimod. Data about a standard treatment are missing in the medical literature; part of it is caused by the existence of a diversity of etiologic agents and clinical forms. The present review summarizes the advances made in the field of CBM related to the diversity of pathogenic species, fungi and host cell relationship, antigens, innate and acquired immunity, clinical forms of CBM, chemotherapy, and diagnosis.

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Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction

Cited by 5 publications

References 64 publications

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

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

Lopinavir-menthol co-crystals for enhanced dissolution rate and intestinal absorption

Reviewing the Etiologic Agents, Microbe-Host Relationship, Immune Response, Diagnosis, and Treatment in Chromoblastomycosis

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