Antiviral research最新文献

{"title":"Discovery of broad-spectrum antivirals targeting viral proteases using in silico structural modeling and cellular analysis","authors":"Dharmeshkumar Patel ,&nbsp;Ramyani De ,&nbsp;Niloufar Azadi ,&nbsp;Sujin Lee ,&nbsp;Savannah Shooter ,&nbsp;Sarah Amichai ,&nbsp;Shaoman Zhou ,&nbsp;Danielle Monroe ,&nbsp;Cameron Mahanke ,&nbsp;Tamara R. McBrayer ,&nbsp;Michael Muczynski ,&nbsp;Abdullah Al-Homoudi ,&nbsp;Joseph Engel ,&nbsp;Yury A. Bochkov ,&nbsp;James E. Gern ,&nbsp;Ladislau C. Kovari ,&nbsp;Franck Amblard ,&nbsp;Raymond F. Schinazi","doi":"10.1016/j.antiviral.2025.106245","DOIUrl":"10.1016/j.antiviral.2025.106245","url":null,"abstract":"<div><div>The development of broad-spectrum antivirals is a high-priority goal to prevent future global outbreaks. Some antiviral agents developed for specific viral protein targets may exhibit broad-spectrum antiviral activity or provide helpful information for broad-spectrum drug development. In this study, we compared the sequence- and structure-based similarity of SARS-CoV-2 3CL^pro with proteases from other viruses and identified 24 proteases with similar active-site structures. Our in-house lead molecules, NIP-22c and CIP-1 were reported as novel peptidomimetic, reversible covalent inhibitors of SARS-CoV-2 3CL^pro with nanomolar potency. Molecular docking of NIP-22c, CIP-1 and nirmatrelvir were performed with structurally similar proteases of different viruses, norovirus, enterovirus and rhinovirus. The predictions were validated with in vitro enzymatic and cell-based assays. As predicted, NIP-22c and CIP-1 showed broad-spectrum antiviral activity with EC₅₀ values in the nanomolar range against SARS-CoV-2, norovirus, enterovirus and rhinovirus by targeting 3CL/3C^pro. In contrast, nirmatrelvir did not show activity up to 10 μM against all three viruses and the mechanism of inactivity of nirmatrelvir was hypothesized through binding pocket analysis using molecular dynamics simulations.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106245"},"PeriodicalIF":4.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739546","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 herpes simplex virus type 1 replication by Pin1 inhibitors: insights from H-77 and novel compounds","authors":"Abeer Mohamed Abdelfattah Elsayed ,&nbsp;Miuko Kurose ,&nbsp;Akifumi Higashiura ,&nbsp;Akima Yamamoto ,&nbsp;Toshihito Nomura ,&nbsp;Takashi Irie ,&nbsp;Masaya Fukushi ,&nbsp;Jeffrey Encinas ,&nbsp;Hisanaka Ito ,&nbsp;Takayoshi Okabe ,&nbsp;Tomoichiro Asano ,&nbsp;Takemasa Sakaguchi","doi":"10.1016/j.antiviral.2025.106244","DOIUrl":"10.1016/j.antiviral.2025.106244","url":null,"abstract":"<div><div>Herpes simplex virus type 1 (HSV-1) infection is widespread globally, necessitating the development of new therapeutic approaches. Previous studies have demonstrated that peptidyl-prolyl cis/trans isomerase Pin1 is essential for the replication of cytomegalovirus, a member of the herpesvirus family. Our research demonstrated that Pin1 knockdown significantly suppressed HSV-1 replication. Furthermore, we found that our Pin1 inhibitor H-77, along with four novel Pin1 inhibitors, also inhibited HSV-1 replication. The 50 % effective concentration (EC₅₀) of H-77 against HSV-1 replication in VeroE6 cells was 0.75 μM. In HSV-1-infected cells treated with H-77, expression levels of the immediate early viral protein ICP0 and late viral proteins VP5 and glycoprotein C (gC) were significantly reduced, indicating suppression of viral protein expression. Immunofluorescence staining revealed that in H-77-treated cells, viral proteins including VP5 were confined within the nucleus by an intact nuclear lamina. Transmission electron microscopy analysis demonstrated that H-77-treated cells exhibited markedly fewer extracellular viral particles, with nucleocapsid nuclear egress being inhibited. These results demonstrate that H-77 suppresses HSV-1 replication through dual mechanisms: inhibition of viral protein synthesis and blockade of nucleocapsid nuclear egress. These findings indicate that Pin1 represents a promising therapeutic target for HSV-1 inhibition, warranting further development of Pin1 inhibitors as anti-HSV-1 agents.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106244"},"PeriodicalIF":4.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714524","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":"Cerebrospinal fluid concentrations, viral suppression and biomarkers with long-acting cabotegravir and rilpivirine intramuscular injections","authors":"Aylin Yilmaz ,&nbsp;Amedeo De Nicolò ,&nbsp;Antonio D'Avolio ,&nbsp;Magnus Gisslén","doi":"10.1016/j.antiviral.2025.106243","DOIUrl":"10.1016/j.antiviral.2025.106243","url":null,"abstract":"<div><div>Our aim was to determine cerebrospinal fluid (CSF) and plasma concentrations of cabotegravir and rilpivirine (CAB/RPV) when administered as long-acting (LA) intramuscular injections every four (Q4W) or eight (Q8W) weeks, and to study the effect on viral suppression and CSF biomarkers of inflammation and neuronal injury. We included six adults with HIV receiving LA CAB/RPV Q4W or Q8W. CSF and plasma concentrations of CAB/RPV (15 samples) were analyzed by UHPLC-MS/MS. We also measured CSF and plasma HIV RNA, CSF and serum neopterin, CSF and serum β2-microglubulin, IgG index, albumin ratio, and CSF NfL. Median (range) total plasma cabotegravir concentrations were 1375 (963–2422) ng/mL, and in CSF 3.48 (1.47–7.60 ng/mL). For rilpivirine, concentrations were 93 (40–157) ng/mL and 1.21 (0.55–1.67) ng/mL, respectively. All participants hade CSF and plasma HIV RNA &lt;20 copies/mL on every occasion. There were no significant changes in any of the CSF biomarkers in participants after switching to LA CAB/RPV. The combination of LA CAB/RPV can achieve therapeutic CSF concentrations throughout the dosing intervals and may suppress HIV replication in the CNS. No significant changes in CSF biomarkers of inflammation or neuronal injury were observed, indicating a neutral CNS effect.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106243"},"PeriodicalIF":4.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717347","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":"Single-dose injection of human neutralizing antibody against ZIKV preserves male fertility and protects against lethal infection","authors":"Hao Zhang ,&nbsp;Ziyang Sheng ,&nbsp;Feiyang Xue ,&nbsp;Han Wang ,&nbsp;Na Gao ,&nbsp;Shiqi He ,&nbsp;Yuetong Li ,&nbsp;Dongying Fan ,&nbsp;Peigang Wang ,&nbsp;Lei Yu ,&nbsp;Jing An","doi":"10.1016/j.antiviral.2025.106240","DOIUrl":"10.1016/j.antiviral.2025.106240","url":null,"abstract":"<div><div>Zika virus (ZIKV) is a mosquito-transmitted flavivirus. Unlike other flavivirus members, ZIKV has a distinct tropism for the reproductive system. Previous studies have demonstrated that ZIKV has adverse impacts on the male reproductive system, particularly in testis and epididymis. However, no specific prophylactic and therapeutic agents are available against ZIKV till now. A human monoclonal antibody, 2B10, has been shown to be protective against microcephaly. Here, we intraperitoneally administered a single injection of 2B10 after ZIKV infection to explore its therapeutic potential on viral damage in testis and epididymis in both IFN-α/β and IFN-γ receptor-deficient (AG6) mouse and IFN-α/β receptor-deficient (A6) mouse models. The results showed that 2B10 significantly decreased the viremia and viral loads in organs in two types of male mice, markedly mitigated ZIKV-induced histo-morphologic disruption and inflammatory infiltration and maintained hormone levels. The integrity of tight junctions in the testis and epididymis was also maintained at normal levels by 2B10 administration. In long-term observation in ZIKV-infected A6 mice, 2B10 could confer effective protection of male fertility. In the AG6 model, 2B10 fully protected mice from lethal challenge. These results suggested that 2B10 provides effective protection in post-exposure therapy for ZIKV infection in mice. Since 2B10 is a human antibody, it might be a promising intervention candidate for maintaining male reproductive health during ZIKV infection in the endemic area.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106240"},"PeriodicalIF":4.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697463","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":"Mammalian-targeted antiviral peptide reduces dengue virus type 1 infection in Aedes aegypti","authors":"Danya Medina-Carrasco ,&nbsp;Glay Chinea Santiago ,&nbsp;Hilda Elisa Garay Pérez ,&nbsp;Gladys Gutiérrez-Bugallo ,&nbsp;Luis Gabriel González-Lodeiro ,&nbsp;Anubis Vega-Rúa ,&nbsp;Vivian Huerta Galindo","doi":"10.1016/j.antiviral.2025.106241","DOIUrl":"10.1016/j.antiviral.2025.106241","url":null,"abstract":"<div><div>Dengue virus is the most important arbovirus for public health worldwide. <em>Aedes aegypti</em> is the DENV primary vector and acquires the virus during blood meal from a viremic human. BCN0941 is a structure-based designed antiviral peptide that inhibits early stages of DENV infection in mammalian cells [WO2015131858A2]. Studies of structure-activity relationship indicate that the molecular target of the antiviral activity of BCN0941 is the Low-density lipoprotein receptor related protein-1 (LRP1), an evolutionary conserved receptor that we have identified as putative DENV receptor in mammalian cells. In this work, we evaluated the antiviral activity of BCN0941 peptide against DENV serotype 1 in mosquito cells. <em>In vitro</em> assays were performed in cell lines C6/36 (<em>Aedes albopictus</em>) and Aag2 (<em>Aedes aegypti</em>)<em>.</em> The antiviral activity <em>in vivo</em> in a metapopulation of field-collected <em>A. aegypti</em> mosquitoes was also evaluated. BCN0941 peptide exhibited the capacity to decrease viral infection in both experimental set up, <em>in vivo</em> and <em>in vitro</em>, up to a 50 % and 60 % of the treatment controls respectively, as determined by immunofluorescence. BCN0941 may be an effective DENV transmission-blocking drug due to its dual action in decreasing the viral load in infected people and the mosquito vector.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106241"},"PeriodicalIF":4.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678857","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":"High-throughput split-GFP antiviral screening assay against fusogenic paramyxoviruses","authors":"Laura Vandemaele ,&nbsp;Thibault Francken ,&nbsp;Joost Schepers ,&nbsp;Winston Chiu ,&nbsp;Niels Cremers ,&nbsp;Hugo Klaassen ,&nbsp;Charlène Marcadet ,&nbsp;Lorena Sanchez Felipe ,&nbsp;Arnaud Marchand ,&nbsp;Patrick Chaltin ,&nbsp;Pieter Leyssen ,&nbsp;Johan Neyts ,&nbsp;Manon Laporte","doi":"10.1016/j.antiviral.2025.106242","DOIUrl":"10.1016/j.antiviral.2025.106242","url":null,"abstract":"<div><div>The paramyxovirus family includes important pathogens such as measles and mumps viruses, as well as emerging pathogens with pandemic potential such as Nipah virus. Despite the threat to public health and the frequent identification of novel paramyxoviruses, no antiviral drugs are currently available. A hallmark of most paramyxoviruses is the induction of cell-cell fusion leading to syncytia formation. To facilitate antiviral drug discovery, we leveraged this trait and established a high-throughput split-green fluorescent protein (GFP) antiviral screening assay suitable for high-content imaging through the quantification of virus-induced GFP⁺ syncytia. The assay was validated with well-known broad-spectrum antiviral compounds against representative members of five different <em>Paramyxovirinae</em> genera. Using this split-GFP assay, a small-molecule repurposing library of approximately 3000 compounds was screened against recombinant Cedar virus (CedV), a nonpathogenic henipavirus. Two molecules were identified: Cathepsin Inhibitor 1 with henipavirus-specific activity and PF-543 with pan-paramyxovirus activity. Both molecules inhibit viral replication by blocking cell-cell fusion. The split-GFP assay presented here will enable the development of extensive drug discovery initiatives aimed at identifying much-needed pan-henipavirus/paramyxovirus inhibitors.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106242"},"PeriodicalIF":4.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697462","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":"Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by its architectural damage and blocking HN protein","authors":"Satyendu Nandy,&nbsp;Siddharth Neog,&nbsp;Sachin Kumar","doi":"10.1016/j.antiviral.2025.106239","DOIUrl":"10.1016/j.antiviral.2025.106239","url":null,"abstract":"<div><div>Cholesterol 25-hydroxylase (CH25H) is a membrane-bound endoplasmic reticulum protein that converts cholesterol into 25-hydroxycholesterol (25HC). Recent studies showed that CH25H is an interferon-stimulated gene (ISG) that helps fight various viruses and has broad antiviral effects. However, the role of chicken CH25H (chCH25H) in controlling Newcastle disease virus (NDV) infection and replication remains unexplored. This study examined the impact of chCH25H on NDV infection in chicken embryo fibroblast cells. The results showed that cells try to upregulate the chCH25H expression temporally upon viral infection. Moreover, the overexpression of chCH25H reduced NDV infection in cells while reducing endogenous chCH25H levels increased its replication. Additionally, treating cells and viruses with 25HC, an active metabolic intermediate of chCH25H, significantly reduced NDV replication by blocking the virus from entering cells while causing significant structural damage to the virus architecture. In addition, <em>in ovo</em> results also exhibited that the eggs treated with lipopolysaccharides (LPS), a positive regulator of chCH25H and 25HC, resulted in extensive viral reduction. These findings indicate that chCH25H and 25HC are against NDV replication in chicken fibroblast cells.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106239"},"PeriodicalIF":4.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673836","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":"Functional characteristics of plitidepsin as an antiviral treatment against monkeypox virus infection","authors":"Guillermo Albericio ,&nbsp;Daniel Rodríguez-Martín ,&nbsp;Pablo Avilés ,&nbsp;Carmen Cuevas ,&nbsp;María J. Guillén-Navarro ,&nbsp;María A. Noriega ,&nbsp;Sara Flores ,&nbsp;Pedro J. Sánchez-Cordón ,&nbsp;David Astorgano ,&nbsp;Patricia Pérez ,&nbsp;Mariano Esteban ,&nbsp;Juan García-Arriaza","doi":"10.1016/j.antiviral.2025.106238","DOIUrl":"10.1016/j.antiviral.2025.106238","url":null,"abstract":"<div><div>Monkeypox virus (MPXV), closely related to variola virus, causes mpox, a zoonotic disease traditionally endemic to Central Africa. However, recent outbreaks have increased human transmission of MPXV clades. In 2022, global MPXV spread was linked to clade IIb, whereas in 2024, the more pathogenic clade Ib became predominant. These trends raised concerns about sustained human transmission, prompting the WHO to declare mpox a Public Health Emergency of International Concern. Despite the availability of smallpox vaccines, their protective efficacy against mpox remains limited. Additionally, the limited efficacy of current smallpox antivirals, such as Tecovirimat and Brincidofovir, alongside growing concerns about the emergency of tecovirimat resistance mutants, underscores the need for new therapeutic options. Given these challenges, novel antiviral strategies with different mechanisms of action are urgently needed to control MPXV outbreaks. Plitidepsin, a cyclodepsipeptide drug initially approved for cancer treatment, has demonstrated potent antiviral activity against multiple viruses by targeting eukaryotic elongation factor 1 alpha (eEF1A). Here, we have evaluated the antiviral activity of plitidepsin against MPXV infection. In cultured cells, plitidepsin exhibited strong antiviral effects, with a favorable therapeutic index and low cytotoxicity. In CAST/EiJ mice, a highly susceptible MPXV model, plitidepsin significantly reduced viral replication in the lungs. Additionally, treated mice displayed a marked reduction in inflammatory lung lesions and proinflammatory cytokines, suggesting immunomodulatory effects. These findings indicate plitidepsin as a promising candidate for mpox treatment. Further studies are needed to explore its potential as a standalone or combination therapy, supporting clinical evaluation for mpox treatment.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106238"},"PeriodicalIF":4.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658230","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":"Pralatrexate effectively inhibits the replication of monkeypox virus in vitro and in vivo","authors":"Jianshu Li ,&nbsp;Siyu Li ,&nbsp;Chaode Gu ,&nbsp;Shaowen Shi ,&nbsp;Xiao Li ,&nbsp;Zhendong Guo ,&nbsp;Zongzheng Zhao ,&nbsp;Miao He ,&nbsp;Zhiwei Wu","doi":"10.1016/j.antiviral.2025.106232","DOIUrl":"10.1016/j.antiviral.2025.106232","url":null,"abstract":"<div><div>The monkeypox virus (MPXV), an orthopoxvirus, has caused a number of major outbreaks and emerged as a global public health threat. Although drugs have been approved for the treatment of mpox, the efficacy and side effects remain unknown, which calls for the development of safe and effective drugs. Pralatrexate (PDX) is a fourth-generation antifolate drug with inhibitory activity against a wide range of viruses. In this study, we demonstrated the antiviral activity of PDX against MPXV <em>in vitro</em> and <em>in vivo</em>. Our results showed that PDX potently inhibited the MPXV replication at very low drug concentrations <em>in vitro</em>, and could significantly inhibit MPXV activity in dormice. In conclusion, this study found that PDX is an effective antiviral drug against MPXV infection, showing potential as a novel therapy for MPXV infection.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106232"},"PeriodicalIF":4.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616058","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":"Generation of a panel of mutants that are resistant to standard of care therapies in a clinically relevant strain of human cytomegalovirus for drug resistance profiling","authors":"Meghan F. Carter,&nbsp;Kassidy Knight,&nbsp;Yetunde Kayode,&nbsp;Eain A. Murphy","doi":"10.1016/j.antiviral.2025.106237","DOIUrl":"10.1016/j.antiviral.2025.106237","url":null,"abstract":"<div><div>Infection with human cytomegalovirus (HCMV) can result in a significant disease burden within the immunosuppressed and immunocompromised patient populations. Current standard of care (SOC) relies on direct-acting antivirals which target a limited group of viral proteins including the viral polymerase (UL54), terminase (UL56), and protein kinase (UL97). Incomplete inhibition of virally encoded proteins result in a selective pressure towards the generation of “breakthrough” drug resistant variants. One limitation in evaluating novel antivirals is the difficulty in profiling their antiviral activity against variants resistant to current SOC interventions, as these resistant variants have arisen in different genetic backgrounds with distinct replication kinetics and yields.</div><div>To limit strain variation we generated a targeted mutant panel of viruses in a bacterial artificial chromosome (BAC) derived clinically relevant laboratory strain of HCMV, TB40e, that expresses the fluorescent proteins mCherry upon viral entry and eGFP at times after viral DNA replication. This unique construct allows for the monitoring of viral entry and viral DNA replication independently. This panel consists of WT and seven mutant viruses harboring mutations that confer resistance to ganciclovir, maribavir, cidofovir, and letermovir. In addition, we characterized a host-targeted sirtuin 2 deacetylase (Sirt2) inhibitor, FLS-359, against the SOC resistant variants. We observed that mutant viruses demonstrated increased EC₅₀ concentrations for SOC inhibition, and that host directed FLS-359 demonstrated broad-spectrum antiviral activity against known SOC drug-resistant mutants. This panel represents a much-needed comparatively innovative platform for screening the efficacy of new direct-acting antivirals and host-directed antivirals against HCMV variants refractive to therapeutic interventions.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106237"},"PeriodicalIF":4.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144623823","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}