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以天冬氨酰蛋白酶为靶点的 HIV 肽酶抑制剂：阻断其酶活性及干扰真菌生长和巨噬细胞相互作用。

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

机构信息

Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos (LTBBF), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.

Laboratório de Microbiologia Celular, IOC/FIOCRUZ, Rio de Janeiro, Brazil.

出版信息

J Enzyme Inhib Med Chem. 2020 Dec;35(1):629-638. doi: 10.1080/14756366.2020.1724994.

DOI:10.1080/14756366.2020.1724994
PMID:32037904
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7034032/
Abstract

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 and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from 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, 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.

摘要

可引起几种人类真菌感染病，主要是着色芽生菌病，该病极难治疗。几项研究表明，人类免疫缺陷病毒蛋白酶抑制剂（HIV-PIs）是抗真菌治疗的有吸引力的候选药物。这项工作集中研究了 HIV-PIs 对 和其分泌的肽酶活性的作用，以及它们对真菌增殖和巨噬细胞相互作用的影响。我们检测到 能够切割白蛋白的肽酶活性，对胃蛋白酶抑制剂 A 和 HIV-PIs（特别是洛匹那韦、利托那韦和阿普那韦）敏感，这首次表明该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降低了真菌生长，导致显著的超微结构改变。洛匹那韦和利托那韦还影响了分生孢子与巨噬细胞的黏附和巨噬细胞的杀伤。有趣的是，利托那韦与伊曲康唑或酮康唑联合使用可抑制 的生长。总的来说，我们的结果支持 HIV-PIs 的抗真菌作用及其作为真菌感染的可能替代治疗方法的相关性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/5f6ba0a57a6e/IENZ_A_1724994_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/9f6fb0b43946/IENZ_A_1724994_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/ddac817ef349/IENZ_A_1724994_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/e8f3229972d9/IENZ_A_1724994_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/f1366dc95368/IENZ_A_1724994_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/5f6ba0a57a6e/IENZ_A_1724994_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/9f6fb0b43946/IENZ_A_1724994_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/ddac817ef349/IENZ_A_1724994_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/e8f3229972d9/IENZ_A_1724994_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/f1366dc95368/IENZ_A_1724994_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce55/7034032/5f6ba0a57a6e/IENZ_A_1724994_F0005_B.jpg

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