{"title":"Apatinib inhibits HTNV by stimulating TFEB-driven lysosome biogenesis to degrade viral protein","authors":"Qikang Ying , Xiaoxiao Zhang , Tianle Gu , Junmei Zhang , Yuhang Dong , Wenjie Feng , Dongjing Li , Xingan Wu , Fang Wang","doi":"10.1016/j.antiviral.2025.106124","DOIUrl":"10.1016/j.antiviral.2025.106124","url":null,"abstract":"<div><div><em>Hantaan Orthohantavirus</em> (Hantaan virus, HTNV) infection causes hemorrhagic fever with renal syndrome (HFRS) in humans, posing a significant health threat. Currently, there are no long-lasting protective vaccines or specific antivirals available, creating an urgent need for effective antiviral treatments in the clinical management of HFRS. Given that viruses exploit multiple host factors for their replication, host-oriented inhibitors could offer promising therapeutic options. In our study, we screened a library of 2570 drugs and identified apatinib, a kinase inhibitor, as a potent suppressor of HTNV infection both <em>in vitro</em> and <em>in vivo</em>. Mechanistic studies revealed that apatinib exerts its antiviral effect by targeting transcription factor EB (TFEB). Specifically, apatinib inhibits the PI3K-Akt signaling pathway and reduces mTOR phosphorylation, which in turn downregulates TFEB phosphorylation. This facilitates the nuclear translocation of TFEB and enhances lysosomal function by upregulating the expression of lysosome-associated genes and promoting lysosome biogenesis. Consequently, there is an increase in lysosome-mediated viral nucleocapsid protein degradation. The ability of apatinib to stimulate this lysosome-driven antiviral mechanism presents a potential new therapeutic approach for viral infections and offers valuable insights into virus-host interactions during HTNV replication.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106124"},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530926","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}
Antiviral researchPub Date : 2025-02-26DOI: 10.1016/j.antiviral.2025.106125
Tenan Zhang , Xiang Chen , Chengcheng Tao , Haojun Huang , Zhi Luo , Mengmeng Liu , Wen Cui , Wei Wang
{"title":"Structural and mechanistic insight into the phosphorylation reaction catalyzed by mpox virus thymidine kinase","authors":"Tenan Zhang , Xiang Chen , Chengcheng Tao , Haojun Huang , Zhi Luo , Mengmeng Liu , Wen Cui , Wei Wang","doi":"10.1016/j.antiviral.2025.106125","DOIUrl":"10.1016/j.antiviral.2025.106125","url":null,"abstract":"<div><div>Mpox virus (MPXV) is the etiological agent of mpox, which is a major threat to human health. The identification of potential drug targets and the development of effective antiviral therapies are still urgently needed. The thymidine kinase (TK) encoded by MPXV initiates the deoxythymidine triphosphate (dTTP) salvage synthesis pathway and facilitates viral DNA replication. MPXV without TK presents significant replication defects. MPXV TK is also responsible for the activation of nucleos(t)ide analogs, which are an important class of antivirals. Despite its importance in the viral life cycle and antiviral development, the structure and catalytic mechanism of MPXV TK are not fully understood. Here, we determined the three-dimensional structure of an MPXV TK variant, in which the glutamic acid at position 83 was substituted with alanine. MPXV TK consists of two domains and forms a tetramer. One protomer binds dTTP with two lassos and a P-loop, while the other protomers are captured in apo-form. Mutation of residues near the dTTP-binding site significantly reduces the catalytic activity of MPXV TK, indicating the importance of these residues in substrate binding and/or catalysis. Specifically, E83 is found to play a crucial role in stabilizing dTTP and lasso II. A biochemical assay confirmed that dTTP functions as a feedback inhibitor of MPXV TK and its inhibitory potency was evaluated. These results may facilitate the discovery of specific inhibitors targeting TK to mitigate MPXV infections.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106125"},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529655","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}
Antiviral researchPub Date : 2025-02-23DOI: 10.1016/j.antiviral.2025.106123
Juliane Brun , Benediktus Yohan Arman , Michelle L. Hill , J.L. Kiappes , Dominic S. Alonzi , Laetitia L. Makower , Karolina D. Witt , Carina Gileadi , Victor Rangel , Raymond A. Dwek , Annette von Delft , Nicole Zitzmann
{"title":"Assessment of repurposed compounds against coronaviruses highlights the antiviral broad-spectrum activity of host-targeting iminosugars and confirms the activity of potent directly acting antivirals","authors":"Juliane Brun , Benediktus Yohan Arman , Michelle L. Hill , J.L. Kiappes , Dominic S. Alonzi , Laetitia L. Makower , Karolina D. Witt , Carina Gileadi , Victor Rangel , Raymond A. Dwek , Annette von Delft , Nicole Zitzmann","doi":"10.1016/j.antiviral.2025.106123","DOIUrl":"10.1016/j.antiviral.2025.106123","url":null,"abstract":"<div><div>The COVID-19 pandemic highlights the need for novel antiviral drug discovery approaches that could dramatically shorten timelines from compound discovery to clinical development. At the beginning of the pandemic, repurposing approaches were at the forefront of early research efforts to screen for antiviral activity against SARS-CoV-2 in over 2500 compounds. Here, we report cellular screening results of 100 FDA-approved and experimental compounds against SARS-CoV-2 in the human Calu-3 cell line. We observed 13 compounds showing antiviral activity against SARS-CoV-2, including seven FDA-approved compounds (remdesivir, boceprevir, amiloride, nafamostat, cisplatin, silmitasertib, and miglustat), and six compounds in pre-clinical and clinical development (tarloxotinib, lucerastat (<em>N</em>B-DGJ), M<em>O</em>N-DNJ, <em>N</em>AP-DNJ, <em>N</em>N-DGJ and <em>N</em>N-DNJ). Further, we observed that our screening hits include several host-targeting antivirals, namely iminosugars, that are largely non-toxic and offer a large therapeutic window. The most-developed iminosugar M<em>O</em>N-DNJ (UV-4B), which has been evaluated in a Phase 1 clinical trial, shows antiviral activity against SARS-CoV-2 wild type as well as alpha, beta, gamma, delta, and Omicron variants. Its activity also extended to another betacoronavirus HCoV OC43, but not alphacoronavirus HCoV 229E. Our cellular screening results add to the body of knowledge on antivirals against coronaviruses and confirm the antiviral efficacy of iminosugars in cellular assays using the human lung-cell line Calu-3.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106123"},"PeriodicalIF":4.5,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antiviral researchPub Date : 2025-02-22DOI: 10.1016/j.antiviral.2025.106122
Jonna B. Westover , Kie Hoon Jung , Shuli Mao , Alexander A. Kolykhalov , Gregory R. Bluemling , Michael G. Natchus , George R. Painter , Brian B. Gowen
{"title":"Oral 4′-fluorouridine rescues mice from advanced lymphocytic choriomeningitis virus infection","authors":"Jonna B. Westover , Kie Hoon Jung , Shuli Mao , Alexander A. Kolykhalov , Gregory R. Bluemling , Michael G. Natchus , George R. Painter , Brian B. Gowen","doi":"10.1016/j.antiviral.2025.106122","DOIUrl":"10.1016/j.antiviral.2025.106122","url":null,"abstract":"<div><div>Lymphocytic choriomeningitis virus (LCMV) can cause severe, life-threatening infection and disease in organ transplant recipients and other immunocompromised individuals. Additionally, significant developmental and neurological disabilities, vision impairments, and miscarriages can occur as a direct result of LCMV infection during pregnancy. Currently, there are no approved antiviral drugs to protect at-risk populations. Here, we report on the potent in vitro activity of the 4′-fluorouridine (4′-FlU) ribonucleoside analog against several strains of LCMV, with EC<sub>90</sub> values in the low micromolar range. In vivo, oral once-daily 4′-FlU treatments provided robust efficacy in mice challenged with LCMV when administered as late as 5 days post-infection. Our findings extend the broad-spectrum antiviral capacity of 4′-FlU and support the compound's further development for treating LCMV and other severe arenavirus infections.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106122"},"PeriodicalIF":4.5,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490519","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":"Research progress of vimentin in viral infections","authors":"Jiawei Zheng , Xue Li , Guoqing Zhang , Ying Ren , Linzhu Ren","doi":"10.1016/j.antiviral.2025.106121","DOIUrl":"10.1016/j.antiviral.2025.106121","url":null,"abstract":"<div><div>Vimentin, a type III intermediate filament protein, has become a focal point in the research of viral infections. It participates in multiple crucial processes during the viral life cycle and the host's antiviral response. During viral entry, it may function as a receptor or co-receptor and interact with viral entry proteins, also influencing endocytic pathways. Furthermore, vimentin engages with replication complexes and modulates the intracellular environment in viral replication. Moreover, vimentin plays significant roles in immune responses and inflammatory reactions during viral infections. This review thoroughly analyzes the recent progress in understanding vimentin's functions during viral infections, covering aspects such as viral entry, replication, and the immune response to achieve a cohesive comprehension of the underlying mechanisms. The antiviral strategies based on vimentin are also discussed, aiming to promote the development of more effective preventive and treatment strategies for viral diseases.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106121"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453950","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}
Antiviral researchPub Date : 2025-02-18DOI: 10.1016/j.antiviral.2025.106120
Danny Ka-Ho Wong , Ning Chow , Hoi Tang Ma , Ka Yan Wong , Lung-Yi Mak , Wai-Kay Seto , Man-Fung Yuen
{"title":"Mechanism of entecavir-induced reduction of HBV DNA integration","authors":"Danny Ka-Ho Wong , Ning Chow , Hoi Tang Ma , Ka Yan Wong , Lung-Yi Mak , Wai-Kay Seto , Man-Fung Yuen","doi":"10.1016/j.antiviral.2025.106120","DOIUrl":"10.1016/j.antiviral.2025.106120","url":null,"abstract":"<div><div>Nucleos(t)ide analogues (NUC) treatment can reduce the extent of HBV DNA integration in chronic hepatitis B (CHB) patients. However, the mechanism by which NUC reduces HBV integration is unclear. This study investigated the effects of entecavir (ETV), one of the commonly used NUC, on cells with HBV integration. Full genome-length HBV DNA was inserted into HepG2 cell genome using the sleeping beauty transposon system. The resulting cells, named HepG2/SB/HBV, was subjected to ETV treatment. In ETV-treated HepG2/SB/HBV, intracellular HBV DNA was reduced by 2-fold. When treated with ETV, HepG2/SB/HBV had an impaired cell survival (25% reduction in cell proliferation rate when compared with untreated cells; p = 0.043). The median integration frequency in untreated HepG2/SB/HBV was 16 integration sites per 10<sup>5</sup> cells, which was reduced to 14.8 integration sites per 10<sup>5</sup> cells when treated with ETV. Analysis of the expression of apoptosis and mitosis markers showed that ETV-treated HepG2/SB/HBV had a reduced expression of mitosis markers phospho-cell division control-2 (p-cdc-2) and phospho-histone H3 (p-histone H3), but that of the apoptotic markers [Poly-ADP-ribose-polymerase] (PARP) and caspase-3 were not affected. In conclusion, ETV suppressed cell proliferation of hepatoma cells with HBV integration via interference of mitosis and reduced expression of p-histone H3, thereby reducing the number of HBV-integrated hepatocytes. This may be the mechanism by which HBV integration is reduced in CHB patients who received ETV therapy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106120"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466660","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 efficiency of high-throughput screening (HTS) and in-silico data analysis during medical emergencies: Identification of effective antiviral 3CLpro inhibitors","authors":"Debora Zian , Daniela Iaconis , Simone Nenci , Alessandra Crusco , Sanjeevani Tawde , Mariangela Sodano , Rocco Vitalone , Ameya Raje , Martina Palamini , Daniele Carettoni , Angela Molteni , Candida Manelfi , Valerio Tazzari , Andrea Rosario Beccari , Paolo Malune , Stefania Maloccu , Annalaura Paulis , Angela Corona , Salvatore Nieddu , Silvano Coletti , MariaPia Catalani","doi":"10.1016/j.antiviral.2025.106119","DOIUrl":"10.1016/j.antiviral.2025.106119","url":null,"abstract":"<div><div>The COVID-19 pandemic highlighted the importance of accelerating the drug discovery process. The 3-chymotrypsin-like protease (3CLpro) is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral replication process and was quickly identified as a prime target for drug development. This study leverages High-Throughput Screening (HTS) to identify novel 3CLpro inhibitors. We screened a different library of 325,000 compounds, leading to the discovery of two new chemical scaffolds with selective inhibitory activity against 3CLpro. <em>In-silico</em> analysis and further experimental validation, elucidated the binding modes and mechanisms of action, revealing a covalent inhibitor targeting the catalytic pocket and two allosteric inhibitors affecting the monomer/dimer equilibrium of 3CLpro. The identified compounds demonstrated significant antiviral activity in vitro, reducing SARS-CoV-2 replication in VeroE6 and Calu-3 cell lines. This study highlights the potential of combining HTS and computational approaches to accelerate the discovery of effective antiviral agents, suggesting a workflow to support the research and the design of effective therapeutic strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106119"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"M49L and other drug resistance mutations emerging in individuals after administration of ensitrelvir in Japanese clinical settings","authors":"Akira Inoue , Takaya Ichikawa , Daiki Wada , Shuhei Maruyama , Haruka Shimazu , Masami Kashihara , Kazuyuki Okuda , Fukuki Saito , Takasuke Fukuhara , Yasushi Nakamori","doi":"10.1016/j.antiviral.2025.106118","DOIUrl":"10.1016/j.antiviral.2025.106118","url":null,"abstract":"<div><div>Recent in-vitro and in-vivo studies and analysis of genomic information registered in GISAID have raised concerns about drug resistance mutations such as M49L after treatment with the 3C-like protease inhibitor ensitrelvir. The aim of this study was to identify resistance gene mutations to 3C-like protease inhibitors, including M49L mutations, in Japanese clinical settings. Genomic analysis of samples from our hospital admissions showed M49L mutations associated with ensitrelvir treatment in three cases and M49L mutation unrelated to ensitrelvir treatment in three cases. In a study of cases with persistent infection or rebound in viral load after 5 days of ensitrelvir treatment, 10 of 16 patients had M49L mutations and 5 had M49I mutations. Resistance gene mutations following treatment with ensitrelvir were shown to emerge even within individual patients who were not immunocompromised. In a study of persistent SARS-CoV-2 infection in severely immunocompromised patients, various drug resistance mutations emerged, with the M49L mutation especially showing a tendency to be a majority mutation. The current status of drug resistance mutations occurring in individuals following administration of ensitrelvir in Japanese clinical settings was clinically investigated for the first time. Considering that the barrier to resistance to ensitrelvir is lower than that to other antiviral drugs and that M49L is a unique mutation that occurs quickly, tends to become a majority mutation, and is maintained thereafter through its ability to replicate, the spread of strains that have acquired ensitrelvir resistance should be closely monitored.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106118"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antiviral researchPub Date : 2025-02-17DOI: 10.1016/j.antiviral.2025.106117
Carolina Q. Sacramento , Ryan Bott , Qinfeng Huang , Brett Eaton , Elena Postnikova , Ahmad J. Sabir , Malaika D. Argade , Kiira Ratia , Manu Anantpadma , Paul R. Carlier , Hinh Ly , Yuying Liang , Lijun Rong
{"title":"Recombinant Pichinde reporter virus as a safe and suitable surrogate for high-throughput antiviral screening against highly pathogenic arenaviruses","authors":"Carolina Q. Sacramento , Ryan Bott , Qinfeng Huang , Brett Eaton , Elena Postnikova , Ahmad J. Sabir , Malaika D. Argade , Kiira Ratia , Manu Anantpadma , Paul R. Carlier , Hinh Ly , Yuying Liang , Lijun Rong","doi":"10.1016/j.antiviral.2025.106117","DOIUrl":"10.1016/j.antiviral.2025.106117","url":null,"abstract":"<div><div>Several arenaviruses, such as the Old World (OW) Lassa virus (LASV) and the New World (NW) Junin virus (JUNV), can cause severe and lethal viral hemorrhagic fevers in humans. Currently, no vaccines or specific antiviral therapies are FDA-approved for treating arenavirus infections. One major challenge for the development of new therapeutic candidates against these highly pathogenic viruses is that they are BSL-3/4 pathogens that need to be handled in high biocontainment laboratories. In this work, a recombinant non-pathogenic New World arenavirus, Pichinde virus (rPICV), was used for the development of a high-throughput screening (HTS) assay in the BSL-2 laboratory for the screening and identification of small molecule inhibitors against arenaviruses. The rPICV is a replication-competent virus expressing the firefly luciferase reporter gene in the infected cells proportionally to the infection rate. rPICV infection was optimized for an automated HTS in 384-well format with robust Z′ scores, high signal-to-background ratios, and low intrinsic variance. Screening an established library allowed for the identification of five top hit compounds, which included ribavirin, a known inhibitor of arenaviral RNA synthesis, showing good potency and selectivity in inhibiting rPICV replication. The antiviral activity of the top hit compounds was further validated against another recombinant arenavirus, the OW lymphocytic choriomeningitis virus (rLCMV) and against laboratory strains of LASV (Josiah) and JUNV (Romero). The use of rPICV in the HTS-based antiviral assay under BSL-2 condition has proven to be safe and suitable for the identification of broad-spectrum small molecule inhibitors against highly pathogenic arenaviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106117"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antiviral researchPub Date : 2025-02-15DOI: 10.1016/j.antiviral.2025.106105
Junyuan Cao , Hao Zhang , Jixiang Zhang , Jinlin Wang , Chen Li , Jin Ma , Zhengyu Ye , Yunting Zheng , Hong Liu , Gengfu Xiao , Wenhao Dai , Leike Zhang
{"title":"Screening of botanical drugs reveals the potential anti-human adenovirus activity of berberine","authors":"Junyuan Cao , Hao Zhang , Jixiang Zhang , Jinlin Wang , Chen Li , Jin Ma , Zhengyu Ye , Yunting Zheng , Hong Liu , Gengfu Xiao , Wenhao Dai , Leike Zhang","doi":"10.1016/j.antiviral.2025.106105","DOIUrl":"10.1016/j.antiviral.2025.106105","url":null,"abstract":"<div><div>Human adenovirus (HAdV) is a significant viral pathogen that causes severe acute respiratory infections (SARIs) in children and immunocompromised patients. Currently, no specific treatment options are available for HAdV infections. This study used a green fluorescence protein-based, high-throughput screening (HTS) assay on a botanical drug library containing 3697 botanical compounds to identify agents that could inhibit HAdV. Four compounds with anti-HAdV-C5 activity in the low-micromolar range were identified and inhibited other wild-type HAdVs known to cause SARIs. Among these compounds, 13-methylberberine chloride presented the highest select index values. Berberine is a commercially available natural product-derived isoquinoline alkaloid with multiple pharmacological effects and is widely used in Asian countries. We systematically evaluated the anti-HAdV activity of six berberine-derived compounds in vitro and performed a time-of-drug-addition assay to explore their antiviral modes of action. Mechanistic studies revealed that berberine and its analogs inhibit HAdV replication by downregulating the MAPK signaling pathway, particularly ERK activation, which is crucial for viral replication and progeny production. Our findings suggest that berberine is a promising candidate for the development of anti-HAdV therapies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106105"},"PeriodicalIF":4.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}