Biomedicine & Pharmacotherapy最新文献

{"title":"Bictegravir decreases expression of system L-amino acid transporters and inhibits leucine uptake activity in a human placental cell line","authors":"Ratul Sabrina Rasna ,&nbsp;Caroline E. Dunk ,&nbsp;Md Tozammel Hoque ,&nbsp;Reina Bendayan ,&nbsp;Lena Serghides","doi":"10.1016/j.biopha.2025.118291","DOIUrl":"10.1016/j.biopha.2025.118291","url":null,"abstract":"<div><div>Antiretroviral therapy (ART) improves maternal health and reduces perinatal HIV transmission; however, it has been associated with increased risk for adverse outcomes via mechanisms that are poorly understood. Branched-chain amino acids (BCAAs) are important for fetal development and cardiometabolic health. Alterations in BCAAs have been reported in pregnant people with HIV and children exposed to ART <em>in utero</em>. System L-amino acid transporters are key in transporting BCAAs across the placenta, but their functionality in the context of ART use has not been investigated. Here we examine the effects of antiretrovirals on the expression and function of system L transporters. Syncytialized BeWo cells were treated with atazanavir, darunavir, efavirenz, dolutegravir, raltegravir, bictegravir or cabotegravir for 24 h at C_max and half C_max therapeutic concentrations. Cytoplasmic and membrane protein expression of system L isoforms were quantified by western blot. System L transport activity was measured using [³H]-tritium-labelled L-leucine uptake assays in the presence or absence of a system L-specific inhibitor. System L isoforms LAT-1 and LAT-2 were primarily expressed in the plasma membrane, whereas LAT-4 expression was predominantly cytoplasmic. Bictegravir significantly reduced the protein levels of all 3 isoforms. Cabotegravir was associated with lower LAT-1 and LAT-4 and efavirenz with lower LAT-1 and LAT-2 levels. A reduction in leucine transport was only observed with bictegravir treatment. Bictegravir, which has been recently added to perinatal treatment guidelines, was associated with downregulation of system L expression and function in BeWo cells. Further <em>in vivo</em> studies are warranted to confirm our findings.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118291"},"PeriodicalIF":6.9,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aqueous extract of Sedum sarmentosum (SS-Ex) promotes bone formation and linear bone growth in a calcium/vitamin D-deficient mouse model","authors":"Dong Ho Jung ,&nbsp;Hye Jin Kim ,&nbsp;Jin Ah Ryuk ,&nbsp;Byoung-Seob Ko ,&nbsp;Yong-Bum Kim ,&nbsp;Chang-Seon Myung ,&nbsp;Wan-Jung Im","doi":"10.1016/j.biopha.2025.118294","DOIUrl":"10.1016/j.biopha.2025.118294","url":null,"abstract":"<div><div>Proper bone development during the growth phase is essential for achieving normal skeletal length, mineral density, and strength, which is regulated by growth hormones, vitamin D, and calcium. Deficiencies in these elements can impair skeletal formation, increasing the risk of disorders such as rickets and osteoporosis. Therefore, natural compounds with bone-supportive effects are of growing interest. <em>Sedum sarmentosum</em> (<em>S</em>. <em>sarmentosum</em>), a plant traditionally used in Korea to treat liver disorders, contains abundant vitamin C and calcium, however, its effects on bone development remain unclear. We found that oral administration of an aqueous extract of <em>S. sarmentosum</em> (SS-Ex) improved trabecular bone structure and bone mineral density in mice fed a calcium- and vitamin D-deficient diet. SS-Ex treated mice showed increased growth plate thickness and elevated serum levels of osteocalcin (Ocn), type I collagen alpha 1 (Col1a1), calcium, and calcitonin. <em>In vitro</em>, SS-Ex enhanced alkaline phosphatase (Alp) activity and promoted mineral deposition in MC3T3-E1 pre-osteoblasts. Additionally, SS-Ex upregulated osteogenic genes including runt-related transcription factor 2, osterix, <em>O</em>cn<!--> <!-->, osteopontin, <em>Alp</em>, and <em>Col1a1</em>. Whereas mechanistically, SS-Ex downregulated the expression of dickkopf-related protein 1, a negative regulator of the wingless-type MMTV integration site (Wnt)/β-Catenin pathway, thereby activating Wnt3a/β-Catenin signaling. Moreover, SS-Ex upregulated the expression of bone morphogenetic protein 2 (Bmp2), further enhancing osteogenic signaling. These findings suggest that SS-Ex promotes osteoblast differentiation, supports linear bone growth <em>via</em> growth plate stimulation, and helps maintain calcium balance, indicating its potential as a natural agent for enhancing bone development during growth.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118294"},"PeriodicalIF":6.9,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-cancer small-molecule Inauhzin-C confines its cytotoxicity to cancer cells by targeting GRP78","authors":"Alexander Mrozek,&nbsp;Nimisha Bhattarai ,&nbsp;Daniel Nguyen ,&nbsp;Shelya X. Zeng,&nbsp;Heewon Park,&nbsp;Hua Lu","doi":"10.1016/j.biopha.2025.118248","DOIUrl":"10.1016/j.biopha.2025.118248","url":null,"abstract":"<div><div>Activation of the unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, upregulates molecular chaperones, such as glucose-regulated protein 78 kDa (GRP78), to promote cellular re-localization and oncogenic signaling. Previously, we demonstrated that nanoparticle encapsulation of INZ-C (n-INZ-C) inhibits cancer cell growth <em>in vitro</em> and <em>in vivo</em> with no toxicity to normal cells. Yet, it remains completely unknown why INZ-C is specifically toxic to cancer cells. In our attempt to address this question, we identified GRP78 as a new target of INZ-C. We showed that INZ-C specifically binds to GRP78 using a combination of proteomic, biophysical, and cell-based approaches. Since GRP78 has been previously shown to translocate to the cell surface in cancer cells, we sought to evaluate the role of GRP78 in the cellular uptake and bioactivity of n-INZ-C. Intriguingly, we found that GRP78 knockdown leads to a significant reduction in cellular uptake and increase in IC₅₀ concentration. Further investigation revealed nuclear translocation of GRP78 following n-INZ-C treatment in cancer cells, but not in normal cells. Taken together, these findings not only unveil GRP78 as a novel target of INZ-C, but also indicate binding to the deregulated cancer cell-surface protein as the possible molecular mechanism underlying cancer cell-specific toxicity of the small molecule. The study also strongly suggests the potential of n-INZ-C as a promising GRP78-targeted anti-cancer therapy and offers a new approach to improve current front-line treatments.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118248"},"PeriodicalIF":6.9,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144365527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual IL-2/IL-21 priming augments the anti-tumor function of CD16V-CAR/TRAIL-engineered NK cells in combination with monoclonal antibodies","authors":"Injung Hwang ,&nbsp;Jinu Lee ,&nbsp;Sae Won Kim ,&nbsp;Young Chul Sung","doi":"10.1016/j.biopha.2025.118289","DOIUrl":"10.1016/j.biopha.2025.118289","url":null,"abstract":"<div><div>The advancement of NK cell-based immunotherapy requires platform-specific approaches that overcome intrinsic functional limitations while enabling flexible adaptation across diverse manufacturing settings. NK101, a human NK cell line phenotypically aligned with the CD56^dimCD62L⁺ intermediate-stage subset, retains functional plasticity and robust cytokine responsiveness, providing a versatile platform for adoptive immunotherapy development. Although baseline cytotoxicity is relatively modest, this profile allows for rational reprogramming through targeted cytokine and genetic interventions. We initiated this reprogramming by screening IL-2 family cytokines for their effects on proliferation and effector molecule production. IL-2 and IL-15 promoted proliferation and IFN-γ secretion, whereas IL-21 uniquely enhanced granzyme B levels with minimal effects on proliferation and IFN-γ. Co-stimulation with IL-2 and IL-21 proved most effective, maximizing cytotoxic potential while sustaining proliferation and enhancing IFN-γ secretion. Transcriptomic profiling further highlighted IL-21’s role in activating granzyme-mediated apoptosis, which was amplified by IL-2 co-priming. These findings were applied to genetically engineered NK101 cells expressing high-affinity CD16 (NK101-16V), where IL-2 and IL-21 co-priming enhanced both baseline cytotoxicity and antibody-dependent cellular cytotoxicity. Additional engineering to express membrane-bound TRAIL (NK101-16V-TR) significantly augmented TRAIL-mediated apoptosis, enabling greater killing of resistant tumors. <em>In vivo</em>, IL-2/IL-21-primed NK101-16V-TR cells in combination with rituximab achieved complete tumor regression in all Jeko-1 xenograft-bearing mice. Collectively, this study presents a broadly applicable design framework for NK cell manipulation, integrating transient cytokine priming with multi-functional genetic modification to guide the development of next-generation NK cell therapies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118289"},"PeriodicalIF":6.9,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyroptosis in acute respiratory distress syndrome and pulmonary fibrosis","authors":"Jinfeng Liao ,&nbsp;Yangbo Liang ,&nbsp;Zheng Liu ,&nbsp;Qin Xie ,&nbsp;Jin-Ming Zhang ,&nbsp;Si-Yuan Song ,&nbsp;Xiaobo Huang ,&nbsp;Luhong Cao ,&nbsp;Yi Wang","doi":"10.1016/j.biopha.2025.118286","DOIUrl":"10.1016/j.biopha.2025.118286","url":null,"abstract":"<div><div>ARDS (acute respiratory distress syndrome) and PF (pulmonary fibrosis) are severe pulmonary conditions with significant morbidity and mortality. This review focuses on the pyroptosis, a lytic, pro-inflammatory form of programmed cell death, as a central mechanism linking these two pathologies. We address how inflammasome activation stimulates the pyroptosis initiation and subsequently releases a cascade of inflammatory cytokines that drive the acute lung injury of ARDS. Subsequently, we elucidate how this sustained pyroptotic inflammation, combined with shifts in macrophage polarization, creates a pro-fibrotic microenvironment that promotes fibroblast activation and extracellular matrix deposition, thereby mechanistically driving the transition from ARDS to PF. The pathological landscape, from the early stage of ARDS to PF, is further shaped by a dynamic interaction between pyroptosis, necroptosis, and ferroptosis, with the temporal dominance of each pathway influencing the progression from acute inflammation to chronic fibrosis. Particularly, the clinical relevance of these mechanisms is also addressed in COVID-19-induced ARDS. Therefore, targeting key regulators of this axis, such as the NLRP3 inflammasome and the effector protein Gasdermin D, presents a promising therapeutic strategy to alleviate inflammatory responses upon tissue damage and halt fibrotic progression, offering new hope for these severe lung diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118286"},"PeriodicalIF":6.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow tumor microenvironment profiling predicts distinct immunosuppressive phenotypes and immunotherapy potential in AML patients","authors":"Leslie Correia da Cruz ,&nbsp;Yejin Lee ,&nbsp;Ji Yeon Paik ,&nbsp;Jeonghye Park ,&nbsp;Marc Diederich ,&nbsp;Claudia Cerella","doi":"10.1016/j.biopha.2025.118287","DOIUrl":"10.1016/j.biopha.2025.118287","url":null,"abstract":"<div><div>The immune landscape of acute myeloid leukemia (AML) is poorly understood, and its myeloid origins complicate the distinction between pathological and immunoregulatory components. We refined the AML microenvironment (AME) classification, demonstrating distinct immunophenotypes from AML lineages and maturation stages. We developed distinct 13-gene megakaryocytic/erythroid (MK/Ery) and 16-gene myelomonocytic/monocytic (ML/Mo) polygenic markers and validated them in adult and pediatric AML patient cohorts, including single-cell RNA-sequencing data. To identify immunoregulatory factors, the AME composition was predicted by the xCell algorithm, immune dysfunction was computed by TIDE, and differential gene expression analyses identified candidate genes. To validate our findings, we studied the effects of MK/Ery-like and ML/Mo-like AML cell lines on CD8⁺ T-cells/AML cells in co-culture assays, using models identified by Celligner matching AML patient blasts. Patients with high MK/Ery expression (MK/Ery^High) exhibited a dysfunctional microenvironment with increased pro-inflammatory cytokines, increased T-cell infiltration, and upregulated immune checkpoints, particularly CD274 (PD-L1). Single-cell RNA-seq confirmed that CD274 overexpression originated from malignant subclones with MK/Ery-like phenotypes. Conversely, AML with high ML/Mo expression (ML/Mo^High) displayed a T-cell-depleted niche enriched in myeloid-derived suppressive elements, including M2 macrophages, VISTA, and galectins. MK/Ery-like (e.g., OCI-M1, HEL) and ML/Mo-like (e.g., MUTZ3, MONO-MAC-1) cells suppressed T-cell proliferation in co-culture. Pharmacological PD-1/PD-L1 blockade with the small-molecule inhibitors BMS-1166 and BMS-1001 abrogated HEL-mediated T-cell proliferation inhibition. Transcriptomic data, single-cell analyses, and functional co-culture experiments reveal two AMEs: T–cell–rich yet dysfunctional vs. myeloid-driven and immunosuppressive. This refined categorization overcomes the traditional hot–cold classification to tailor future AML immunotherapies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118287"},"PeriodicalIF":6.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144365356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mTOR pathway in Gliomas: From molecular insights to targeted therapies","authors":"Safura Pournajaf ,&nbsp;Mohammad Hossein Pourgholami","doi":"10.1016/j.biopha.2025.118237","DOIUrl":"10.1016/j.biopha.2025.118237","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor with extreme aggressiveness, poor prognosis, and a high mortality rate. To maintain a high rate of proliferation and invasion, GBM cells manipulate many biological processes within the cell and the tumor microenvironment, including intracellular signaling pathways. One of the main signaling pathways with proven roles in GBM pathology is the PI3K/AKT/mTOR signaling pathway, with its molecular alterations considered a hallmark of GBM. Through integrating with various upstream signals from growth factors, nutrients, and energy status, regulatory feedback mechanisms with other signaling pathways, manipulation of glioma stem cells, and epigenetic regulations, this pathway contributes to GBM cell proliferation, growth, angiogenesis, and metastasis, and more importantly escape the effects of available therapies. The extent of involvement of the PI3K/AKT/mTOR signaling pathway grants a more delicate and detailed understanding of this pathway.</div><div>This review provides a deep insight into the mTOR pathway in GBM, revealing its modulators and interactions with upstream and downstream regulators. It also provides comprehensive information on the latest mTOR-targeted therapies and resistance mechanisms.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118237"},"PeriodicalIF":6.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated CCL20 and IL-10 enhance 5-fluorouracil tolerance in colon cancer","authors":"Janani Muralidharan ,&nbsp;Murugesh Eswaran ,&nbsp;Sejong Bae ,&nbsp;Shailesh Singh ,&nbsp;Hina Mir","doi":"10.1016/j.biopha.2025.118258","DOIUrl":"10.1016/j.biopha.2025.118258","url":null,"abstract":"<div><div>Conventional chemotherapeutics for colon cancer often fail to achieve optimal clinical outcomes, as many patients develop resistance and experience significant toxicity, thereby increasing the overall health burden. Understanding the mechanisms conferring resilience to cancer cells is essential for developing more effective therapies. 5-Flourouracil (5FU) is the standard of care used for colon cancer. 5FU-associated inflammation, characterized by a change in cytokine profile, enables the colon cancer cells to evade cell death, thereby undermining the cytotoxic effects of the drug. Current study underscores the significance of CCL20 signaling, which is linked to inflammatory conditions and is elevated during colon carcinogenesis, in tempering the cytotoxic effects of 5FU. The presented data demonstrate an inverse correlation between CCL20 concentrations in colon cancer and sensitivity to 5FU. Moreover, treatment with 5FU further stimulates CCL20 signaling in colon cancer cells, likely via increased fatty acid efflux. Notably, the findings reveal that IL10 signaling is under negative regulation of CCL20. Additionally, exposure to 5FU elevates IL10 levels, thus creating a complex interplay of pro-inflammatory and anti-inflammatory pathways. Such dual activation of contrasting mechanisms undermines the therapeutic efficacy of 5FU. Therefore, the insights gained from this study emphasize the significance of addressing immune signatures characterized by CCL20 and IL10 to enhance the effectiveness of 5FU in colon cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118258"},"PeriodicalIF":6.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antroquinonol mitigates Tau hyperphosphorylation, neuronal damage and cognitive impairments in a chronic cerebral ischemia rat model","authors":"Ling-Yu Yang ,&nbsp;Chiu-Hao Hsu ,&nbsp;Ya-Wen Cheng ,&nbsp;Kuo-Wei Chen ,&nbsp;Sheng-Che Chou ,&nbsp;Yong-Ren Chen ,&nbsp;Yi-Tzu Chen ,&nbsp;Chuan-Rou Deng ,&nbsp;I.-Chin Chen ,&nbsp;Meng-Fai Kuo ,&nbsp;Kuo-Chuan Wang","doi":"10.1016/j.biopha.2025.118271","DOIUrl":"10.1016/j.biopha.2025.118271","url":null,"abstract":"<div><div>Chronic cerebral ischemia (CCI) induced hyperphosphorylated Tau has been associated with an increased risk of neurodegenerative disorders such as Alzheimer’s and vascular dementia. This study investigated the neuroprotective effects of Antroquinonol (AQ), an ubiquinone derivative from Antrodia camphorata with anti-inflammatory and antioxidant properties. Bilateral internal carotid artery ligation (BICAL) in male Wistar rats and mixed rat primary neuron/glia co-cultures exposed to a hypoxia and hypoglycemia (HH) environment were used as experimental CCI models to investigate the therapeutic effects and mechanisms of AQ. AQ was administered daily at low or high doses for 28 days after BICAL induction. Two and four weeks after BICAL surgery, the functional and cognitive outcomes were evaluated by rotarod test, open field test (OFT), novel object recognition (NOR) and Y-maze test. Nissl, TUNEL, IHC and ICC staining, and Western blot analysis were used to evaluate the effects and underlying mechanisms of AQ in the treatment of CCI. The results showed that both low and high doses of AQ treatment significantly ameliorated motor deficits, anxiety-like behavior, and cognitive impairments in BICAL rats at 2 or 4 weeks post-CCI. Histological and molecular analyses revealed that AQ reduced neuronal injury, microglia activation, apoptosis, and Tau hyperphosphorylation in the cortex and hippocampus regions. We also found that AQ inhibited HH-induced hyperphosphorylation of Tau by modulating protein kinases (p-GSK3β Y216 and p-mTOR), LC3II, and p-NRF2 proteins in cultured cells, suggesting roles in kinase regulation, autophagy, and antioxidation. These findings support AQ as a promise therapeutic candidate for treating CCI-related neurodegenerative disorders.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118271"},"PeriodicalIF":6.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies","authors":"Wen-Fang Tang ,&nbsp;Hui-Ping Tsai ,&nbsp;Yuan-Fan Chin ,&nbsp;Shan-Ko Tsai ,&nbsp;Cheng-Chin Lin ,&nbsp;Son Tung Ngo ,&nbsp;Po-Huang Liang ,&nbsp;Jia-Rong Jheng ,&nbsp;Chung-Fan Hsieh ,&nbsp;Jin-Ching Lee ,&nbsp;Yu-Hsiu Chang ,&nbsp;Tein-Yao Chang ,&nbsp;Chia-Yi Lin ,&nbsp;Guan-Hua Lin ,&nbsp;Jie-Yun Cai ,&nbsp;Yu-Li Chen ,&nbsp;Yuan-Siao Chen ,&nbsp;Ping-Cheng Liu ,&nbsp;Chuen-Mi Yang ,&nbsp;Tolou Shadbahr ,&nbsp;Jim-Tong Horng","doi":"10.1016/j.biopha.2025.118252","DOIUrl":"10.1016/j.biopha.2025.118252","url":null,"abstract":"<div><div>The rapid mutation rate of SARS-CoV-2 highlights the urgent need for continuous drug development to enhance both efficacy and safety. BPR2-D2, an angular coumarin derivative, has previously shown notable anti-influenza activity and broad-spectrum inhibitory effects against RNA viruses. In this study, we found that BPR2-D2 exhibits potent antiviral activity against multiple SARS-CoV-2 variants, including several variants of concern, at nanomolar concentrations. Notably, BPR2-D2 effectively disrupted viral RNA and protein synthesis in infected cells while mitigating pro-inflammatory cytokines triggered by viral replication. Our investigation of SARS-CoV-2 RdRp activity employed <em>in silico</em> analyses, including molecular docking, dynamic simulations, and binding free energy calculations. BPR2-D2 demonstrated superior binding affinity to the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 compared to remdesivir. Additionally, it exhibited an increased synergistic inhibitory activity against the viral enzyme when combined with remdesivir. Both cell-based and <em>in vitro</em> enzyme-based RdRp reporter assays validated BPR2-D2’s capacity to inhibit SARS-CoV-2 RdRp activity. The potential synergistic interaction between BPR2-D2 and remdesivir was investigated using cell-based combination assays. The results revealed a synergistic effect in reducing SARS-CoV-2 RNA synthesis, consistent with the <em>in silico</em> analysis. Collectively, these findings suggest that BPR2-D2, a repurposed small-molecule compound, effectively inhibits SARS-CoV-2 by modulating its RdRp function. This positions BPR2-D2 as a promising novel antiviral agent, while also providing insights into the complex molecular mechanisms underlying viral replication.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118252"},"PeriodicalIF":6.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}