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.

中文翻译：

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疣状毛霉的天冬氨酸肽酶作为 HIV 肽酶抑制剂的靶标：阻断其酶活性并干扰真菌生长和巨噬细胞相互作用。

疣状瓶霉会引起多种人类真菌疾病，主要是染色芽生菌病，这种疾病极难治疗。多项研究表明，人类免疫缺陷病毒肽酶抑制剂（HIV-PI）是抗真菌疗法的有吸引力的候选药物。这项工作的重点是研究 HIV-PI 对 P. verrucosa 分泌的肽酶活性的作用及其对真菌增殖和巨噬细胞相互作用的影响。我们检测到 P. verrucosa 的肽酶活性，能够裂解白蛋白，对胃酶抑素 A 和 HIV-PI，特别是洛匹那韦、利托那韦和安普那韦敏感，首次表明这种真菌分泌天冬氨酸型肽酶。此外，洛匹那韦、利托那韦和奈非那韦减少了真菌生长，导致显着的超微结构改变。洛匹那韦和利托那韦还影响分生孢子-巨噬细胞的粘附和巨噬细胞的杀伤。有趣的是，利托那韦联合伊曲康唑或酮康唑可抑制疣状疟原虫的生长。总的来说，我们的结果支持 HIV-PI 的抗真菌作用及其作为真菌感染的可能替代疗法的相关性。