Antiviral research最新文献

{"title":"SARS-CoV-2 resistance analyses from the Phase 3 BIRCH study of obeldesivir in high-risk nonhospitalized participants with COVID-19","authors":"Charlotte Hedskog ,&nbsp;Lauren Rodriguez ,&nbsp;Yu Hu ,&nbsp;Jiani Li ,&nbsp;Dong Han ,&nbsp;Nadine Peinovich ,&nbsp;Clarissa Martinez ,&nbsp;Pui Yan Ho ,&nbsp;Jason K. Perry ,&nbsp;Juan María González Del Castillo ,&nbsp;Yiannis Koullias ,&nbsp;Ross Martin ,&nbsp;Robert H. Hyland","doi":"10.1016/j.antiviral.2026.106351","DOIUrl":"10.1016/j.antiviral.2026.106351","url":null,"abstract":"<div><div>Obeldesivir is an oral nucleoside analog prodrug that targets and inhibits the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated the development of obeldesivir resistance in participants from the Phase 3, multicenter, double-blind BIRCH study. High-risk, nonhospitalized adults with COVID-19 were randomized to receive obeldesivir or placebo twice daily for 5 days. Mid-turbinate nasal swab samples were collected on Days 1 (baseline), 3, 5, 10, and 15. Amino acid substitutions were identified using deep sequencing and phenotyped using a replicon system. Of the 465 participants randomized and treated, 252 (obeldesivir, 190; placebo, 62) met the sequencing analysis criteria and had sequencing data at baseline. Phenotypic analysis of the 5 Nsp12 substitutions observed at baseline resulted in half-maximal effective concentration (EC₅₀) fold changes ≤1.8 relative to the wildtype reference, indicating no change in susceptibility to obeldesivir. Among participants with baseline and postbaseline sequencing data, 12/73 (16.4 %) and 5/54 (9.3 %) participants in the obeldesivir and placebo groups, respectively, had emergent Nsp12 substitutions. Nine emergent Nsp12 substitutions were detected in the obeldesivir group postbaseline that were not observed in the placebo group. Of these, only 1 substitution (V792I) observed in 1 participant from the obeldesivir group demonstrated a low-level reduction in susceptibility to obeldesivir (EC₅₀ fold change, 4.01). This substitution was first detected on Day 15, and the participant was never hospitalized. The low-to-no change in obeldesivir susceptibility among the treatment-emergent Nsp12 substitutions indicates a high barrier to the development of obeldesivir resistance in high-risk, nonhospitalized patients with COVID-19.</div><div>Clinicaltrials.gov identifier: NCT05603143.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106351"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017287","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":"Hepatitis C virus elimination: So close, so far?","authors":"Jean-Michel Pawlotsky","doi":"10.1016/j.antiviral.2026.106360","DOIUrl":"10.1016/j.antiviral.2026.106360","url":null,"abstract":"<div><div>The advent of highly effective direct-acting antivirals (DAAs) has transformed hepatitis C virus (HCV) infection into a curable disease, with cure rates exceeding 95% across viral genotypes and clinical settings. Along with simplified, short-course treatment regimens and significant advancements in diagnostic technologies, these therapeutic breakthroughs have made eliminating HCV as a public health concern, as defined by the World Health Organization, a realistic goal. However, despite this progress, global advances toward elimination have fallen short of expectations. This review examines why HCV elimination appears to be within reach yet remains elusive. First, the molecular virology of HCV and the pharmacological rationale underlying modern DAA combination therapies are summarized to highlight how complementary antiviral mechanisms and high genetic barriers to resistance enable definitive virological cure. Then, the key factors limiting the translation of individual-level cures into population-level impact are analyzed. Persistent transmission in high-risk and marginalized populations, including people who inject drugs, incarcerated individuals, and men who have sex with men, continues to drive new infections. Incomplete case identification, losses along the care cascade, reinfection in the absence of protective immunity, and the lack of a prophylactic vaccine further constrain treatment-based prevention strategies. Structural and systemic barriers, including stigma, criminalization, inequitable access to diagnostics and treatment, fragile health systems, and uneven political commitment, exacerbate these challenges, particularly in low- and middle-income countries. Eliminating HCV will require sustained political commitment, equitable scaling up of testing and treatment, integration of care into primary and community-based services, robust harm reduction interventions, and coordination.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106360"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123602","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":"Nicotinamide-based Sirtuin 2 inhibitors as anti-HCMV agents","authors":"Dariya Begum,&nbsp;Teng Ai,&nbsp;Daniel J. Wilson,&nbsp;Liqiang Chen,&nbsp;Robert J. Geraghty","doi":"10.1016/j.antiviral.2026.106356","DOIUrl":"10.1016/j.antiviral.2026.106356","url":null,"abstract":"<div><div>Human cytomegalovirus (HCMV) is a prevalent herpesvirus pathogen and remains a significant cause for mortality and morbidity in immunocompromised individuals and newborns. Like all viruses, HCMV uses host cellular proteins to facilitate virus replication and spread. Sirtuin 2 (SIRT2) is an NAD⁺-dependent deacetylase with a variety of substrates, including α-tubulin, where acetylation can alter function and stability. We have previously developed small molecule inhibitors targeting SIRT2 and in the current study, we show that two new compounds inhibit SIRT2 activity and also inhibit HCMV replication. The combination of these SIRT2 inhibitors with standard antivirals such as ganciclovir or letermovir resulted in a generally additive profile. Using indirect immunofluorescence, we determined that SIRT2 and SIRT1 expression was reduced over time in compound treated and untreated cells. We also observed SIRT2 and SIRT1 expression was increased in HCMV infected cells, compared to surrounding uninfected cells, regardless of compound treatment. GAPDH expression was stable over time and did not increase in HCMV infected cells, indicating a possible sirtuin-specific mechanism for upregulation of SIRT2 and 1 expression in infected cells. Further investigation is required to better understand the underlying anti-HCMV mechanism of action for our SIRT2 inhibitors and how HCMV infection impacts SIRT2 expression.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106356"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046029","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":"SARS-CoV-2 resistance analyses from the Phase 3 OAKTREE study of obeldesivir in low-risk nonhospitalized participants with COVID-19","authors":"Lauren Rodriguez ,&nbsp;Yu Hu ,&nbsp;Jiani Li ,&nbsp;Dong Han ,&nbsp;Nadine Peinovich ,&nbsp;Clarissa Martinez ,&nbsp;Pui Yan Ho ,&nbsp;Jason K. Perry ,&nbsp;Ross Martin ,&nbsp;Onyema Ogbuagu ,&nbsp;Amos Lichtman ,&nbsp;Robert H. Hyland ,&nbsp;Charlotte Hedskog","doi":"10.1016/j.antiviral.2025.106339","DOIUrl":"10.1016/j.antiviral.2025.106339","url":null,"abstract":"<div><div>Obeldesivir is an oral nucleoside analog prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated baseline and treatment-emergent viral resistance to obeldesivir in participants from OAKTREE, a multicenter, double-blind trial wherein nonhospitalized adolescents and adults with COVID-19 at low risk of developing severe disease were randomized 1:1 to receive obeldesivir or placebo twice daily for 5 days. Deep sequencing was performed on mid-turbinate nasal swab samples collected on Days 1 (baseline), 3, 5, 10, 15, 20, and 29 from participants who met sequencing analysis criteria. Amino acid substitutions detected in the SARS-CoV-2 replication complex components were phenotyped in a replicon system. Overall, 1425 participants (obeldesivir, 725; placebo, 700) met sequencing analysis criteria and had baseline sequencing data. Thirty-five baseline Nsp12 substitutions, including P323L and G671S, were observed in ≥3 participants. Phenotyping of baseline Nsp12 substitutions showed obeldesivir half-maximal effective concentration (EC₅₀) fold changes relative to wildtype that were within assay variability (≤2.15-fold). Among participants with baseline and postbaseline sequencing data, the proportion of emergent Nsp12 substitutions was similar between groups (obeldesivir, 35/208 [16.8 %]; placebo, 23/120 [19.2 %]). Twenty-five emergent Nsp12 substitutions were detected in the obeldesivir group but not in the placebo group. Only 1 emergent Nsp12 substitution (C799F) from 1 participant in the obeldesivir group was associated with reduced obeldesivir susceptibility, with a 3.35-fold change in EC₅₀ versus wildtype. The low-to-no change in obeldesivir susceptibility among treatment-emergent Nsp12 substitutions indicated a high barrier to development of obeldesivir resistance in low-risk, nonhospitalized patients with COVID-19. <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> identifier: NCT05715528.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106339"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877575","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":"Prophylactic intranasal administration of bacterial lysate OM-85 mitigates human rhinovirus (RV-A1b) lung infection and inflammation in mice","authors":"Sabine Wronski ,&nbsp;Helena Obernolte ,&nbsp;Dirk Schaudien ,&nbsp;Armin Braun ,&nbsp;Katherina Sewald ,&nbsp;Anne Vaslin Chessex ,&nbsp;Edouard Baulier ,&nbsp;Christian Pasquali","doi":"10.1016/j.antiviral.2026.106362","DOIUrl":"10.1016/j.antiviral.2026.106362","url":null,"abstract":"<div><div>Rhinovirus (RV), a common cold virus, is a predominant circulating virus which is increasingly recognized for its contribution to severe respiratory tract infections. Given the lack of vaccines, bacterial lysates are a promising alternative to prevent recurrent respiratory tract infections. OM-85, a bacterial lysate from 21 respiratory bacteria, has long been used safely as an oral drug to prevent recurrent respiratory tract infections in clinics. However, with inhalation emerging as preferred route to directly target the site of airway infection, OM-85 is being developed for local administration in the respiratory tract to enhance mucosal immunity.</div><div>This study evaluated the prophylactic efficacy of intranasally administered OM-85 in a murine model of RV infection. Mice were treated over a period of 12 days prior to RV infection and the immune response and viral load were assessed.</div><div>Intranasal administration of OM-85 primed the host immune response by the recruitment of innate immune cells to the lung, resulting in enhanced viral clearance. This was accompanied by a modulation of the RV-induced immune response toward a less pro-inflammatory phenotype, marked by substantial reduction of pro-inflammatory cytokines and neutrophil infiltration. The immune response was shifted towards an anti-inflammatory state supporting control of inflammation. Complementary precision-cut lung slice experiments confirmed the initial immune-priming activity of OM-85 independent of RV infection.</div><div>These findings demonstrate that local administration of OM-85 in the airways effectively primes the innate immune response and confers mucosal protective effects against RV-induced respiratory tract infection.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106362"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140872","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":"SOX6 is a novel host factor that promotes hepatitis B virus replication by enhancing the transcriptional activity of enhancer I","authors":"Yarong Song ,&nbsp;Yitong Zeng ,&nbsp;Han Zheng ,&nbsp;Shu Shi ,&nbsp;Zhongqing Li ,&nbsp;Mingchen Liu ,&nbsp;Sijin Shao ,&nbsp;Ziheng Luo ,&nbsp;Yurong Li ,&nbsp;Jie Li ,&nbsp;Kuanhui Xiang ,&nbsp;Jie Wang","doi":"10.1016/j.antiviral.2026.106359","DOIUrl":"10.1016/j.antiviral.2026.106359","url":null,"abstract":"<div><div>Chronic hepatitis B virus (HBV) infection is a major global health problem. Currently, existing antiviral drugs are difficult to achieve a functional cure for chronic hepatitis B (CHB). Therefore, it is necessary to develop new antiviral targets, especially those that can directly target HBV covalently closed circular DNA (cccDNA) in hepatocytes. Here, we identified a conserved SOX6 binding site in the enhancer I (ENI) region of the HBV genome, and found that SOX6 promotes the replication of multiple genotypes HBV through its HMG domain. Mechanistically, SOX6 binds to the conserved binding site located in the HBV ENI region through its HMG domain, thereby promoting HBV replication by enhancing the transcriptional activity of ENI. Moreover, cisplatin and doxorubicin not only promote HBV replication but also promote SOX6 expression. Knocking down the expression of endogenous SOX6 or mutating the SOX6 binding site in the HBV ENI region significantly weakens the direct promoting effect of cisplatin and doxorubicin on HBV replication. In summary, SOX6 promotes HBV replication by enhancing the transcriptional activity of HBV ENI through its HMG domain, suggesting that it can serve as a potential target for regulating HBV cccDNA transcription. In addition, SOX6 participates in the direct promotion of HBV replication by cisplatin and doxorubicin, providing new insights into the molecular mechanisms of tumor chemotherapy related HBV reactivation (HBVr) and potential targets for the prevention of HBVr during tumor chemotherapy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106359"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091873","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":"Update on the molecular and cellular biology of hepatitis E virus and therapeutic opportunities","authors":"Laura Corneillie,&nbsp;Léa Mézière,&nbsp;Claire Montpellier,&nbsp;Benjamin Drouet,&nbsp;Cécile-Marie Aliouat-Denis,&nbsp;Laurence Cocquerel","doi":"10.1016/j.antiviral.2026.106353","DOIUrl":"10.1016/j.antiviral.2026.106353","url":null,"abstract":"<div><div>Hepatitis E virus (HEV) is an emerging zoonotic pathogen and the leading cause of acute viral hepatitis worldwide. Nevertheless, HEV remains largely underestimated and poorly controlled. HEV infects a broad range of host species, transmits through diverse routes and can cause chronic infections in immunocompromised individuals and severe hepatitis in pregnant women. Currently, there is no HEV-specific antiviral treatment available and the only licensed vaccine is restricted to a few countries. Taken together, this highlights its significance as a global health treat and underscores the urgent need for new preventive and therapeutic strategies.</div><div>This review provides a comprehensive overview of HEV molecular and cellular biology with a focus on antiviral opportunities. First, we summarize the epidemiology and clinical spectrum of HEV infection, as well as the current prevention, vaccination and treatment strategies. Next, we review the molecular mechanisms underlying HEV entry, replication, and assembly/egress, detailing host and viral factors that represent promising antiviral targets. We present the available <em>in vitro</em> and <em>in vivo</em> experimental models that are essential for studying the HEV life cycle and evaluating therapeutic candidates.</div><div>Particular attention is given to recent discoveries in HEV entry pathways, the organization and functions of the ORF1 replicase complex, and host-virus interactions. Importantly, we provide an up-to-date overview of host-targeting antivirals (HTAs) and direct-acting antivirals (DAAs) against HEV that have been identified so far. This review emphasizes how fundamental virology informs drug discovery and paves the way toward the development of effective antivirals against this underestimated pathogen of increasing global concern.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106353"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028413","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":"Acute management of measles: A systematic review of therapeutic strategies","authors":"Amandeep Kaur ,&nbsp;Ugo Alaribe ,&nbsp;Joseph Varon ,&nbsp;Sidra Hassaan ,&nbsp;Matthew Halma","doi":"10.1016/j.antiviral.2026.106361","DOIUrl":"10.1016/j.antiviral.2026.106361","url":null,"abstract":"<div><div>Measles remains one of the most contagious viral infections, and its resurgence due to declining global vaccination coverage has renewed interest in therapeutic and preventive strategies. This systematic review analyzes current and emerging acute therapies and their relationship to measles virology and clinical outcomes. A systematic search of PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and Google Scholar (1990–2025) was conducted using predefined inclusion and exclusion criteria to identify clinical studies on acute measles treatment. Despite being used off-label, ribavirin and interferon-α have demonstrated reductions in severity and complications in small clinical trials and case reports. Vitamin A supplementation remains the only widely recommended therapy with strong evidence for reducing morbidity and mortality, particularly in children with deficiency. Traditional Chinese medications such as Tanreqing and Xiyanping show symptomatic improvement but require mechanistic validation. Investigational therapeutics, including polymerase inhibitors such as ERDRP-0519, monoclonal antibodies targeting the fusion protein, and antiviral candidates such as remdesivir, offer promising future options. While vaccination remains essential, adjunctive therapies provide additional tools to reduce complications in under-vaccinated populations.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106361"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117608","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":"Nipah virus-derived defective interfering particles generated using non-infectious viral replicon particles confer protective efficacy comparable to those produced with standard full-length infectious virus","authors":"Stephen R. Welch ,&nbsp;Jessica R. Spengler ,&nbsp;Sarah C. Genzer ,&nbsp;Jessica R. Harmon ,&nbsp;JoAnn D. Coleman-McCray ,&nbsp;Teresa E. Sorvillo ,&nbsp;Stuart T. Nichol ,&nbsp;Christina F. Spiropoulou","doi":"10.1016/j.antiviral.2025.106337","DOIUrl":"10.1016/j.antiviral.2025.106337","url":null,"abstract":"<div><div>Defective interfering particles (DIPs) are naturally occurring virus-like particles containing truncated fragments of the parental viral genome and have gained interest as potential medical countermeasures (MCMs) against viral infections. Using the Syrian hamster model of Nipah virus (NiV) disease, we previously showed that treatment with artificially produced NiV-derived DIPs markedly reduced clinical signs and mortality. However, DIP production required infectious NiV and BSL-4 containment, creating a major barrier to clinical translation. Here, we describe an improved, non-infectious, BSL-2-compatible NiV replicon system for DIP generation that eliminates the need for infectious virus. DIPs produced using this system inhibited virus <em>in vitro</em> and retained full protective efficacy in hamsters. By removing the requirement for high-containment virus, this approach overcomes key regulatory and practical hurdles, enabling advancement of DIP-based therapeutics toward clinical evaluation and eventual use against NiV and related henipaviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106337"},"PeriodicalIF":4.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826728","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 phospho-dynamics of cytomegalovirus capsid interaction, with its protein kinase and nuclear egress complex, provide an antiviral targeting concept","authors":"Julia Tillmanns ,&nbsp;Christina Wangen ,&nbsp;Pia Geiger ,&nbsp;Sigrun Häge ,&nbsp;Tihana Lenac Roviš ,&nbsp;Philipp Arnold ,&nbsp;Heinrich Sticht ,&nbsp;Manfred Marschall","doi":"10.1016/j.antiviral.2025.106335","DOIUrl":"10.1016/j.antiviral.2025.106335","url":null,"abstract":"<div><div>Human cytomegalovirus (HCMV) is a major pathogen with worldwide distribution. Improved insight into antiviral targeting is urgently needed for drug development. Viral nuclear capsid egress is a validated target for new small molecules, including the approved viral kinase inhibitor maribavir (MBV). A detailed understanding of the regulatory interplay between HCMV kinase activity (pUL97), the nuclear egress complex (NEC), and viral capsids is pertinent in this regard. Specifically, the egress-based protein–protein interactions represent a virus rate-limiting determinant. The conserved process of nuclear capsid egress is defined by the interaction between the capsid and NEC, as well as an essential regulatory impact of pUL97 phosphorylation. Using recombinant virus analysis systems, we demonstrated the proteins responsible for NEC–capsid binding. The data indicated that the core NEC component pUL53 acts as the primary capsid interactor. Importantly, MBV revealed a dependence on phosphorylation for individual steps in these interactive processes. Of particular note, we used the highly selective mode of MBV in the study to identify pUL97 as a key factor in the regulation of NEC–capsid interaction. The findings also included the direct pUL97–capsid association, as supported by data from protein assembly assays, <em>in vitro</em> kinase reactions, comprehensive microscopy, and bioinformatic modeling of available structures. Finally, the determination of phosphorylated versus nonphosphorylated states of involved proteins led to a more refined understanding of the mechanistic concept of HCMV nuclear capsid egress. Combined, the study may improve our understanding of viral replication efficacy and mechanisms of antiviral drug activity.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"246 ","pages":"Article 106335"},"PeriodicalIF":4.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803033","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}