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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 629 - 638
• Main Authors: Granato, Marcela Q., Sousa, Ingrid S., Rosa, Thabatta L. S. A., Gonçalves, Diego S., Seabra, Sergio H., Alviano, Daniela S., Pessolani, Maria C. V., Santos, André L. S., Kneipp, Lucimar F.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Amprenavir; Antifungal activity; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspartic Acid Proteases - antagonists & inhibitors; Aspartic Acid Proteases - metabolism; aspartic peptidase; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; cellular interaction; Chromoblastomycosis; Chromomycosis; Conidia; Dose-Response Relationship, Drug; Enzymatic activity; Fungi; Furans; HIV; HIV peptidase inhibitors; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Itraconazole; Ketoconazole; Lopinavir; Lopinavir - chemical synthesis; Lopinavir - chemistry; Lopinavir - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Microbial Sensitivity Tests; Molecular Structure; Nelfinavir; Peptidase; Phialophora - drug effects; Phialophora - enzymology; Phialophora - growth & development; Phialophora verrucosa; Research Paper; Ritonavir; Ritonavir - chemical synthesis; Ritonavir - chemistry; Ritonavir - pharmacology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Chromoblastomycosis; HIV peptidase inhibitors; aspartic peptidase; cellular interaction; antifungal activity
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2020.1724994

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.