Schroeder Josefine, Westhoff Jan, Vilotijević Ivan, Werz Oliver, Hoeppener Stephanie, Löffler Bettina, Fischer Dagmar, Ehrhardt Christina
Section of Experimental Virology, Institute of Medical Microbiology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans Knoell-Str. 2, 07745 Jena, Germany.
Division of Pharmaceutical Technology and Biopharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Cauerstr. 4, 91058 Erlangen, Germany.
Int J Mol Sci. 2025 Apr 29;26(9):4235. doi: 10.3390/ijms26094235.
Influenza A virus (IAV) infections continue to threaten public health. Current strategies, such as vaccines and antiviral drugs, are limited due to their time-consuming development and drug-resistant strains. Therefore, new effective treatments are needed. Here, virus-supportive cellular factors are promising drug targets, and the encapsulation of candidate substances in poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) is intended to improve their bioavailability. This study investigates the potential of the indirubin derivative 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE), a glycogen synthase kinase 3 (GSK-3)β inhibitor, for its potential to regulate IAV replication in vitro. The effects of 6BIGOE-loaded PLGA NPs on cell metabolism were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays in A549 and Calu-3 cells. Viral replication and spread were monitored in various IAV-infected cell lines in the absence and presence of free and 6BIGOE-loaded PLGA NPs via plaque assays and Western blot analysis. The encapsulation of 6BIGOE in PLGA NPs resulted in reduced negative side effects on cell viability while maintaining antiviral efficacy. Both encapsulated and free 6BIGOE exhibited antiviral activity, potentially through GSK-3β inhibition and the disruption of key signaling pathways required for viral replication. The data indicate 6BIGOE, particularly after encapsulation in NPs, as a potential candidate for further investigation and development as an antiviral agent to treat IAV infections.
甲型流感病毒（IAV）感染持续威胁着公众健康。目前的策略，如疫苗和抗病毒药物，由于其开发耗时且存在耐药菌株，因而具有局限性。因此，需要新的有效治疗方法。在此，病毒支持性细胞因子是很有前景的药物靶点，将候选物质包裹在聚（D，L-乳酸-乙醇酸）（PLGA）纳米颗粒（NPs）中旨在提高其生物利用度。本研究调查了靛玉红衍生物6-溴靛玉红-3'-甘油肟醚（6BIGOE），一种糖原合酶激酶3（GSK-3）β抑制剂，在体外调节IAV复制的潜力。通过在A549和Calu-3细胞中进行3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）和乳酸脱氢酶（LDH）测定，评估了负载6BIGOE的PLGA NPs对细胞代谢的影响。通过空斑试验和蛋白质免疫印迹分析，在有无游离的和负载6BIGOE的PLGA NPs的情况下，监测了各种IAV感染细胞系中的病毒复制和传播情况。将6BIGOE包裹在PLGA NPs中可减少对细胞活力的负面副作用，同时保持抗病毒功效。无论是包裹的还是游离的6BIGOE都表现出抗病毒活性，可能是通过抑制GSK-3β以及破坏病毒复制所需的关键信号通路来实现的。数据表明6BIGOE，特别是在包裹在NPs中后，作为一种潜在的候选药物，有待进一步研究和开发作为治疗IAV感染的抗病毒剂。
