1. Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction.
- Author
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Granato MQ, Sousa IS, Rosa TLSA, Gonçalves DS, Seabra SH, Alviano DS, Pessolani MCV, Santos ALS, and Kneipp LF
- Subjects
- Antifungal Agents chemical synthesis, Antifungal Agents chemistry, Aspartic Acid Proteases metabolism, Carbamates chemical synthesis, Carbamates chemistry, Carbamates pharmacology, Dose-Response Relationship, Drug, Furans, HIV Protease Inhibitors chemical synthesis, HIV Protease Inhibitors chemistry, Humans, Lopinavir chemical synthesis, Lopinavir chemistry, Lopinavir pharmacology, Macrophages metabolism, Microbial Sensitivity Tests, Molecular Structure, Phialophora enzymology, Phialophora growth & development, Ritonavir chemical synthesis, Ritonavir chemistry, Ritonavir pharmacology, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Sulfonamides pharmacology, Antifungal Agents pharmacology, Aspartic Acid Proteases antagonists & inhibitors, HIV Protease Inhibitors pharmacology, Macrophages drug effects, Phialophora drug effects
- Abstract
Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.
- Published
- 2020
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