Antiviral research最新文献

{"title":"Tirofiban protects mice against severe RSV pneumonia by potentially inhibiting platelet activation via the GPIbα–vWF pathway","authors":"Yu-Si Luo ,&nbsp;Huyan Shen ,&nbsp;Ping Ling ,&nbsp;Han Gao ,&nbsp;Hong Peng ,&nbsp;Haiyan Zhou ,&nbsp;You Dai ,&nbsp;Pingping Zhang ,&nbsp;Fang Chen ,&nbsp;Siyu Lin ,&nbsp;Jin-Fu Li ,&nbsp;Yan-Fei Qi ,&nbsp;Zhongshan Cheng ,&nbsp;Gang Liu ,&nbsp;Ke Zhang","doi":"10.1016/j.antiviral.2025.106207","DOIUrl":"10.1016/j.antiviral.2025.106207","url":null,"abstract":"<div><div>This study aimed to investigate the role of platelets in mediating lethal respiratory syncytial virus (RSV) infection and to explore the potential of antiplatelet therapy as a novel therapeutic approach for RSV infection. <em>Ex vivo</em> and <em>in vivo</em> experiments were used to study the effects of lethal RSV infection on platelet activation, aggregation, and thrombus formation. The emerging therapeutic effect of tirofiban, a GPIIb/IIIa inhibitor, in mitigating RSV-induced pneumonia was also evaluated. Mice infected with a highly virulent RSV strain (R96-5) developed severe RSV pneumonia and showed significantly increased mortality rates, along with extensive platelet infiltration and thrombus formation in the lungs. In situ hybridization revealed co-localization of RSV nucleocapsid RNA with the platelet GPIbα gene in lung tissue. RSV infection induced marked platelet aggregation through the GPIbα-vWF pathway. Notably, tirofiban significantly protected mice from severe pneumonia caused by R96-5. These findings highlight the critical involvement of platelet activation and aggregation in RSV infection and suggest that targeting platelet through the GPIbα–vWF signaling axis may represent a promising therapeutic strategy for severe RSV infection.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106207"},"PeriodicalIF":4.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212136","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":"Broad spectrum antiviral BDGR-164 provides protection against lethal neurotropic alphavirus infection in mice","authors":"Evan P. Williams ,&nbsp;Yi Xue ,&nbsp;Dong Yang ,&nbsp;Jasper Lee ,&nbsp;Eunjung Kim ,&nbsp;Alexander Ponce-Flores ,&nbsp;Lillian Zalduondo ,&nbsp;Xufeng Cao ,&nbsp;Donghoon Chung ,&nbsp;Jennifer E. Golden ,&nbsp;Bernd Meibohm ,&nbsp;Elizabeth A. Fitzpatrick ,&nbsp;Scott C. Weaver ,&nbsp;Colleen B. Jonsson","doi":"10.1016/j.antiviral.2025.106206","DOIUrl":"10.1016/j.antiviral.2025.106206","url":null,"abstract":"<div><div>The New World alphaviruses, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and western equine encephalitis virus (WEEV), cause febrile illness that can progress to fatal disease in humans and equids. As there are no therapeutics approved for the treatment of neurotropic alphavirus disease in humans, we report a structurally novel, quinazolinone, BDGR-164, with nanomolar potency against VEEV, EEEV, and WEEV. Using an intranasal route of virus infection in a lethal BALB/c model, to model aerosol infection in a biodefense scenario, prophylactic subcutaneous administration of BDGR-164 conferred 100 % (VEEV), 88 % (EEEV), and 63 % survival (WEEV) compared to uniform lethality in sham-treated animals. Using RNA-Seq and histopathology, we determined that viral RNA levels and antigen were reduced significantly in the brains of mice from the virus-infected, BDGR-164-treated group as compared to virus-infected, sham-treated group. Moreover, there was a significant reduction in the virus-infected, BDGR-164-treated mice in their host immune responses associated with inflammatory signaling, immune cell recruitment, and programmed cell death. Comparison of cytokines in sera from VEEV-, EEEV- or WEEV-infected mice with and without BDGR-164-treatment suggested that lower levels of IL-6, TNF-α, and RANTES levels correlated with protection and may serve as useful early biomarkers in treatment studies in animal models. In conclusion, our studies show broad and potent prophylactic efficacy of BDGR-164 against neurotropic alphaviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106206"},"PeriodicalIF":4.5,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204788","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":"Identification of pan-flavivirus compounds from drug repurposing","authors":"Fatima Zahra Lissane Eddine ,&nbsp;Gregory Mathez ,&nbsp;Vincent Carlen ,&nbsp;Isabela Dolci ,&nbsp;Rafaela Sachetto Fernandes ,&nbsp;Andre Schutzer Godoy ,&nbsp;Benoît Laleu ,&nbsp;Valeria Cagno","doi":"10.1016/j.antiviral.2025.106205","DOIUrl":"10.1016/j.antiviral.2025.106205","url":null,"abstract":"<div><div>The incidence of orthoflavivirus infections is on the rise, yet effective antivirals are unavailable for all members of this family. Additionally, new orthoflaviviruses are emerging, highlighting the need for antiviral strategies with a pan-flavivirus activity. In response, the Global Health Priority Box was screened, leading to the identification of a compound with pan-flavivirus activity. This hit compound demonstrated inhibition of viral replication, consistent efficacy across various cell lines, and maintained activity even at high multiplicity of infection. Importantly it has a high barrier to resistance and possibly acts through a novel mechanism of action. Due to these attributes and its favorable in vitro ADMET profile, compound MMV1791425 emerges as a promising candidate for the future development of a pan-flavivirus antiviral.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106205"},"PeriodicalIF":4.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198118","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":"Suppression of poxvirus replication by SC144","authors":"Anil Pant ,&nbsp;Djamal Brahim Belhaouari ,&nbsp;Lara Dsouza ,&nbsp;Lalita Priyamvada ,&nbsp;Ziyue Wang ,&nbsp;Santiago Navarro-Forero ,&nbsp;Panayampalli S. Satheshkumar ,&nbsp;Zhengqiang Wang ,&nbsp;Zhilong Yang","doi":"10.1016/j.antiviral.2025.106204","DOIUrl":"10.1016/j.antiviral.2025.106204","url":null,"abstract":"<div><div>Poxviruses are a significant threat to the health of human and economically important animals. Although smallpox, one of the most devastating infectious diseases, is eradicated, the rapid rise of mpox and other poxviral diseases call for the development of antivirals. Here, we show that SC144, a reported small molecule inhibitor of cellular gp130 pathway, suppresses the replication of monkeypox, cowpox, and vaccinia viruses in cultured cells. Interestingly, SC144 likely suppresses vaccinia virus replication independent of gp130. We further show that this suppression of poxvirus replication is achieved by inhibiting viral DNA replication. With EC₅₀ in sub-micromolar range and CC₅₀ of over 250 μM, SC144 is potent and selective, making it a promising candidate for further development as an antiviral against poxviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106204"},"PeriodicalIF":4.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190041","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":"Immunostimulatory effects of multiple short-hairpin RNAs enhance foot-and-mouth disease vaccine-induced humoral immunity","authors":"Aro Kim,&nbsp;Ji-Hyeon Hwang,&nbsp;Gyeongmin Lee,&nbsp;Jong-Hyeon Park,&nbsp;Min Ja Lee,&nbsp;Su-Mi Kim","doi":"10.1016/j.antiviral.2025.106202","DOIUrl":"10.1016/j.antiviral.2025.106202","url":null,"abstract":"<div><div>Small interfering RNAs are typically used to block gene expression via the sequence-specific degradation of mRNA. We previously developed a recombinant adenovirus expressing three short hairpin RNAs, targeting foot-and-mouth disease virus (FMDV) driven by the U6 promoter (Ad-3siRNA). These exhibited rapid antiviral effects against FMDV. Herein, we investigated the immunostimulatory effects of Ad-3siRNA in combination with an FMD inactivated vaccine. Ad-3siRNA induced various cytokines, including type I interferon, and upregulated interferon-stimulated genes in swine cells. Using the combination of Ad-3siRNA and a foot-and-mouth disease (FMD) inactivated vaccine, we observed enhanced protection efficacy until 1 week post-vaccination and enhanced neutralizing antibody levels from 1 week post-vaccination in mice. Furthermore, humoral immunity was significantly enhanced in pigs injected with a vaccine and a combination of Ad-3siRNA for 7 weeks post-vaccination. Ad-3siRNA induced various cytokines, such as IFN-α, IFN-γ, IL-12, IL-6, IL-15 and IL-18, in mice. In conclusion, we demonstrated that Ad-3siRNA, a novel immunostimulatory RNA delivered by a human adenoviral vector, could enhance protection and humoral immunity in combination with an FMD-inactivated vaccine. Exploring the applications of Ad-3siRNAs against other viral diseases and further detailed mechanistic studies are warranted.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106202"},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180748","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":"Long-term effects of peginterferon-based therapy versus nucleos(t)ide analogue monotherapy in non-cirrhotic HBeAg-positive chronic hepatitis B patients","authors":"Qiankun Hu ,&nbsp;Xueyun Zhang ,&nbsp;Xiongyue Cao ,&nbsp;Shuai Tao ,&nbsp;Chong Chen ,&nbsp;Mengxin Lu ,&nbsp;Conglin Zhao ,&nbsp;Liang Chen ,&nbsp;Qiang Li ,&nbsp;Xun Qi ,&nbsp;Yuxian Huang","doi":"10.1016/j.antiviral.2025.106192","DOIUrl":"10.1016/j.antiviral.2025.106192","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>The long-term clinical benefits of interferon (IFN)-based therapy compared to nucleos(t)ide analogue (NA) monotherapy in HBeAg-positive chronic hepatitis B (CHB) have not been well defined. This study aimed to evaluate the cumulative incidence of new-onset cirrhosis, serological responses, and hepatocellular carcinoma (HCC) development between these treatment strategies.</div></div><div><h3>Methods</h3><div>Two independent cohorts of non-cirrhotic, HBeAg-positive CHB patients were analyzed: a treatment-naïve cohort (n = 686) and an NA-experienced cohort (n = 531). Patients received either IFN-based therapy or NA monotherapy. Propensity score matching (PSM) was employed to minimize intergroup heterogeneity. The primary endpoint was the cumulative incidence of new-onset cirrhosis.</div></div><div><h3>Results</h3><div>After PSM, the 10-year cumulative incidence of new-onset cirrhosis was significantly lower in the IFN-based therapy group compared to the NA monotherapy group in both the treatment-naïve (3.3 % vs 20.0 %, <em>p</em> = 0.005) and NA-experienced (4.9 % vs 20.9 %, <em>p</em> = 0.034) cohorts. IFN-based therapy also resulted in significantly higher serological response rates across both cohorts, including HBeAg loss (treatment-naïve: 84.7 % vs 55.6 %; NA-experienced: 60.4 % vs 43.6 %, both <em>p</em> &lt; 0.001) and HBsAg loss (treatment-naïve: 14.3 % vs 5.7 %, <em>p</em> = 0.006; NA-experienced: 10.2 % vs 1.3 %, <em>p</em> &lt; 0.001). Subgroup analysis showed that patients receiving IFN-based therapy who achieved HBeAg loss within 96 weeks had the greatest long-term benefits, with lower cirrhosis incidence and higher HBsAg loss rates. Although the incidence of HCC was lower in the IFN-based group, the difference did not reach statistical significance (both <em>p</em> &gt; 0.05).</div></div><div><h3>Conclusions</h3><div>IFN-based therapy provides superior long-term benefits over NA monotherapy in reducing cirrhosis risk and enhancing serological responses in HBeAg-positive CHB patients.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106192"},"PeriodicalIF":4.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126440","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":"Therapeutic determinants of melatonin in hepatitis caused by coxsackievirus B3 infection","authors":"Sheng-Yu You ,&nbsp;Li-Chiu Wang ,&nbsp;Huey-Pin Tsai ,&nbsp;Yin-Ping Teresa Teng ,&nbsp;Shun-Hua Chen ,&nbsp;Shih-Min Wang","doi":"10.1016/j.antiviral.2025.106191","DOIUrl":"10.1016/j.antiviral.2025.106191","url":null,"abstract":"<div><div>Coxsackievirus B (CVB) is the most recognized enteroviruses associated with acute hepatitis in neonates. It may develop into life-threatening fulminant hepatitis and disseminated intravascular coagulation. Melatonin is a potential agent against infection by modulating inflammation, apoptosis, and oxidative stress. The effect of melatonin on CVB3 replications, cytokine and chemokine productions, and liver damage in CVB3-infected Huh-7 and HepG2 cells were determined. A CVB3-infected hepatitis mouse model was used to explore antiviral, anti-inflammatory, anti-apoptotic, and immunomodulatory responses of melatonin treatment. Melatonin administration reduced viral proteins and viral titers in CVB3-infected cell lines. The expressions of Nrf2 and MST1 were increased, and the levels of cleaved caspase-9 and interleukin (IL)-1β were decreased after melatonin treatment. Melatonin decreased the mortality rate and clinical scores and improved liver damage markers in CVB3-infected mice. Melatonin treatment significantly decreased the viral loads in the liver, spleen, brain, and brain stem of CVB3-infected mice. In the liver of CVB3-infected mice, the expression of Nrf2 and MST1 was increased. Melatonin increased the levels of interferon (IFN)-γ and decreased the levels of IL-1β, IL-6, TNF-α, IL-10, RANTES, and MCP-1 in the serum of CVB3-infected mice. The monocyte expressions were increased after the melatonin treatment of CVB3-infected mice initially. The expressions of the T cells, NK cells, and dendritic cells were attenuated after melatonin treatment through course. Melatonin highlighted the antiviral, anti-inflammatory, anti-oxidative and immune regulatory responses against CVB3-infected hepatitis <em>in vitro</em> and <em>in vivo</em>. The clinical potential efficacy of melatonin treatment in CVB3-infected hepatitis is positive and convinced.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106191"},"PeriodicalIF":4.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107086","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":"Mode of antiviral action of the galactose-specific lectin, AJLec, on the Junin virus propagation","authors":"Shuzo Urata ,&nbsp;Meion Lee ,&nbsp;Tomoko Tsuruta ,&nbsp;Reo Igarashi ,&nbsp;Kohsuke Takeda ,&nbsp;Hideaki Unno","doi":"10.1016/j.antiviral.2025.106189","DOIUrl":"10.1016/j.antiviral.2025.106189","url":null,"abstract":"<div><div>Junin virus (JUNV), a member of <em>Arenaviridae</em>, is the causative agent of Argentine hemorrhagic fever (AHF). Available AHF treatments are limited; therefore, development of effective and safe treatments is required. Thus, in this study, novel lectins were examined for anti-JUNV activity. To evaluate JUNV propagation, a recombinant Junin virus vaccine strain (r3Candid #1/ZsGreen) containing the ZsGreen gene as a marker in the viral genome was used. The anti-JUNV effects of four types of marine organism-derived lectins collected in Japan, including the Nagasaki Prefecture, were examined. AJLec, which was extracted from the Sea Anemone <em>Anthopleura japonica</em>, reduced the number of infected cells and viral production. Infection and infection-surrogate assays revealed that incubation of AJLec with viruses and cells before infection, and maintaining it during infection, was required to exhibit full antiviral activity. Moreover, the anti-JUNV activity of AJLec was suppressed by the addition of lactose; hence, the anti-JUNV activity of AJLec was a result of its galactose recognition. This indicates the importance of galactose on the surface of the Junin virion and the cell membrane for entry into cells. Overall, these results provide new insights into the anti-JUNV activity of AJLec. Particularly, the potential of lectins as new antiviral agents that inhibit pathogenic arenavirus replication and propagation is promising.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106189"},"PeriodicalIF":4.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092722","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":"Structural characterization of HIV fusion inhibitor LP-98: Insights into antiviral and resistance mechanisms","authors":"Nian Liu ,&nbsp;Yuanmei Zhu ,&nbsp;Huihui Chong ,&nbsp;Sheng Cui ,&nbsp;Yuxian He","doi":"10.1016/j.antiviral.2025.106190","DOIUrl":"10.1016/j.antiviral.2025.106190","url":null,"abstract":"<div><div>LP-98 is a lipopeptide-based HIV fusion inhibitor with exceptional potency and long-acting antiviral activity, currently in phase II clinical trials. In this study, we elucidated the structural basis of LP-98's antiviral activity and resistance mechanisms. Using AlphaFold3, we first predicted the six-helical bundle (6-HB) structure formed by LP-98 and the gp41-derived NHR peptide N44, identifying key residues mediating interhelical interactions. Subsequent crystallographic analysis of the LP-98/N44 complex confirmed these binding features, revealing that a cluster of hydrophobic residues in LP-98, along with a network of 15 hydrogen bonds, two electrostatic interactions and a salt bridge, critically stabilizes the 6-HB structure. Superposition analyses of the LP-98/N44 crystal structure with either the predicted 6-HB model or the LP-40/N44 crystal structure provided further mechanistic insights into LP-98's binding mode. Additionally, structural and functional characterization of the N-terminal Tyr-127 residue using a truncated variant (LP-98-Y) demonstrated its essential role in inhibitor binding and antiviral activity. Notably, LP-98 exhibited significantly reduced efficacy against T20-resistant HIV strains harboring single or double mutations in NHR. Our structural models shed light on the molecular basis of this resistance, offering critical insights for drug optimization. Collectively, these findings provide a detailed structural understanding of LP-98's antiviral mechanism, supporting its continued development as a promising next-generation HIV fusion inhibitor.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106190"},"PeriodicalIF":4.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089075","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":"Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo","authors":"Sam Verwimp ,&nbsp;Jessica Wagoner ,&nbsp;Elijah Gabriela Arenas ,&nbsp;Lander De Coninck ,&nbsp;Rana Abdelnabi ,&nbsp;Jennifer L. Hyde ,&nbsp;Joshua T. Schiffer ,&nbsp;Judith M. White ,&nbsp;Jelle Matthijnssens ,&nbsp;Johan Neyts ,&nbsp;Stephen J. Polyak ,&nbsp;Leen Delang","doi":"10.1016/j.antiviral.2025.106186","DOIUrl":"10.1016/j.antiviral.2025.106186","url":null,"abstract":"<div><div>Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable. We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) <em>in vitro</em> and <em>in vivo</em>. We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis. In human skin fibroblasts, synergistic antiviral effects were observed for combinations of MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver cells, FAV + MPV conferred additive to synergistic activity against VEEV and SINV, while SOF synergized with FAV against SINV. In mice, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titres. Combination treatment with MPV and SOF significantly reduced swelling and infectious titres compared to monotherapies of each drug. Sequencing of CHIKV RNA from joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to monotherapy with several higher doses of MPV. Combining these approved oral nucleoside analogues confers potent suppression of multiple alphaviruses <em>in vitro</em> and <em>in vivo</em> with enhanced control of viral genetic evolution in face of antiviral pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106186"},"PeriodicalIF":4.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072362","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}