内生真菌链格孢PO4PR2的次生代谢产物对HIV-1整合酶链转移的突变耐受性抑制
{"_":"Mutation-Tolerant Inhibition of HIV-1 Integrase Strand Transfer by Secondary Metabolites from the Endophytic Fungus PO4PR2.","i":["Alternaria alternata"]}
摘要(中文译文)
内生真菌是新型抗病毒化合物的有前景的来源，来自PO4PR2的粗提物此前已显示出抗HIV-1活性。本研究评估了其对整合酶链转移抑制剂（INSTI）耐药HIV-1的效力及其作用机制。通过定点诱变将关键耐药突变（Y143H、G118R、N155H和R263K）引入HIV-1 pNL4.3克隆，并通过Sanger测序确认。在TZM-bl细胞中评估病毒感染性，同时使用MTT法测定细胞毒性。通过基于荧光素酶的试验测定抗病毒活性，并使用整合酶活性试验和巢式PCR评估整合抑制作用。该提取物对耐药突变体表现出强效抑制作用，IC值较低（0.02971-0.1652 μg/mL），并显示出极低的细胞毒性（CC = 300 μg/mL），细胞活力维持在80%以上。它抑制整合酶活性达67%，特异性靶向链转移步骤，并显著减少整合的病毒DNA。对14种化合物的分子对接鉴定出香豆素衍生物为关键生物活性代谢物，其在整合酶催化口袋内表现出耐受突变的结合能力。总体而言，这些发现凸显PO4PR2作为开发靶向耐药HIV-1整合酶新疗法的化合物有前景的来源。
Abstract
Endophytic fungi are promising sources of novel antiviral compounds, and the crude extract from PO4PR2 has previously shown anti-HIV-1 activity. This study evaluated its efficacy against integrase strand-transfer inhibitor (INSTI)-resistant HIV-1 and its mechanism of action. Key resistance mutations (Y143H, G118R, N155H, and R263K) were introduced into the HIV-1 pNL4.3 clone via site-directed mutagenesis and confirmed through Sanger sequencing. Viral infectivity was assessed in TZM-bl cells, while cytotoxicity was measured using an MTT assay. Antiviral activity was determined through a luciferase-based assay, and integration inhibition was evaluated using integrase activity assays and nested PCR. The extract demonstrated potent inhibition of resistant mutants, with low IC values (0.02971-0.1652 μg/mL), and showed minimal cytotoxicity (CC = 300 μg/mL), maintaining over 80% cell viability. It inhibited integrase activity by 67%, specifically targeting the strand-transfer step, and significantly reduced integrated viral DNA. Molecular docking of 14 compounds identified coumarin derivatives as key bioactive metabolites, exhibiting mutation-tolerant binding within the integrase catalytic pocket. Overall, these findings highlight PO4PR2 as a promising source of compounds for developing new therapies targeting drug-resistant HIV-1 integrase.
如何引用
AMA
Ndzalo Mashabela, Darian Naidu, Ernest Oduro-Kwateng, Nompumelelo P Mkhwanazi. {"_":"Mutation-Tolerant Inhibition of HIV-1 Integrase Strand Transfer by Secondary Metabolites from the Endophytic Fungus PO4PR2.","i":["Alternaria alternata"]}. Microorganisms. 2026; doi:10.3390/microorganisms14051102.
APA
Ndzalo Mashabela, Darian Naidu, Ernest Oduro-Kwateng, Nompumelelo P Mkhwanazi (2026). {"_":"Mutation-Tolerant Inhibition of HIV-1 Integrase Strand Transfer by Secondary Metabolites from the Endophytic Fungus PO4PR2.","i":["Alternaria alternata"]}. Microorganisms. https://doi.org/10.3390/microorganisms14051102
GB/T 7714
Ndzalo Mashabela, Darian Naidu, Ernest Oduro-Kwateng, Nompumelelo P Mkhwanazi. {"_":"Mutation-Tolerant Inhibition of HIV-1 Integrase Strand Transfer by Secondary Metabolites from the Endophytic Fungus PO4PR2.","i":["Alternaria alternata"]}[J]. Microorganisms, 2026 doi:10.3390/microorganisms14051102.
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