Antiviral research最新文献

{"title":"Modeling neurotropic virus infection with functional human neural spheroids as a platform for high-throughput antiviral screening and pathogenesis.","authors":"Angelica Medina, Yu-Chi Chen, Jiajing Zhang, Sarah C Ogden, Samantha Cotsmire, Harshad D Vishwasrao, Marc Ferrer, Emily M Lee","doi":"10.1016/j.antiviral.2025.106248","DOIUrl":"10.1016/j.antiviral.2025.106248","url":null,"abstract":"<p><p>Neurotropic arboviruses pose significant threats to human health due to their ability to infect the central nervous system (CNS). Despite the significant impact on public health, mechanisms underlying neuropathogenesis remains poorly understood, and the development of effective antivirals has been hampered by the lack of predictive, high-throughput (HT) infection platforms that can replicate in vivo disease features to drive early drug discovery. To address this gap, we developed a human-based, HT-compatible, functional viral disease neural spheroid model assembled from human induced pluripotent stem cell (hiPSC)-differentiated neurons and astrocytes as a platform for studying virus infection and the development of HT screening (HTS)-compatible assays for drug discovery. Here, we investigated eight high impact species belonging to either the Bunyaviricetes class or Togaviridae family and evaluated infectability on neural spheroids, followed by characterization of neural activity dysregulation and induced disease. We found that neural spheroids support productive infection, with virus- and time-dependent changes in disease profiles. Transcriptomic changes induced by two representative members, LACV and CHIKV, revealed a highly pro-inflammatory response in LACV infected spheroids whereas CHIKV-infection induced neurodegenerative profiles. Finally, we evaluated antiviral and anti-neural dysfunction activity of interferon-alpha as well as tested the small molecule gemcitabine against CHIKV as a proof-of-concept for HT antiviral compound screening. Together, our data establishes the viral-neural spheroids as a valuable platform that supports productive infection by high impact neurotropic viruses, and this platform can be used to both investigate viral pathogenesis and support therapeutics discovery and development.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106248"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774555","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":"Small molecule direct-acting antivirals for treatment of mpox","authors":"E. Randall Lanier,&nbsp;Richard L. Mackman,&nbsp;Lee Ruggiero,&nbsp;James F. Demarest,&nbsp;John C. Pottage Jr.,&nbsp;INTREPID Alliance Scientific Working Group","doi":"10.1016/j.antiviral.2025.106285","DOIUrl":"10.1016/j.antiviral.2025.106285","url":null,"abstract":"<div><div>In 2022 and 2024, outbreaks of mpox disease caused by two different clades of MPXV resulted in the World Health Organization (WHO) declaring two public health emergencies of international concern (PHEIC). Different clades/subclades/lineages of MPXV can have substantially different pathogenicity and transmission characteristics. The recent rapid spread of mpox disease, evidence for evolution of MPXV during sustained human-human transmission, challenges associated with MPXV vaccination, and disappointing results from two Phase 3 trials of a promising antiviral (tecovirimat) highlight an urgent unmet need for mpox treatments. This review assesses the current landscape of small molecule direct acting antivirals (DAAs) for mpox in the context of potential pandemic threats from ORPVs. Despite many reports of compounds with antiviral activity against MPXV and other ORPVs in vitro, none have proven effective so far in controlled clinical human studies. To address this gap, tecovirimat is undergoing further testing in Phase 3 trials for mpox, as is a second small molecule DAA (brincidofovir), both approved by national regulatory agencies (e.g., U.S. FDA) for the treatment of smallpox based on efficacy in animal models. Additional DAAs for treatment of mpox are in early development, highlighting a major gap in medical countermeasures. Compound characteristics are identified that should increase the probability of clinical success and durability for mpox and improve the likelihood that they will also be effective against other ORPVs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106285"},"PeriodicalIF":4.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211510","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":"Intranasal vaccine induces broad and long-lasting immunity against the hemagglutinin stem of group 2 influenza A viruses","authors":"Wanyue Zhang ,&nbsp;Jérémie Prévost ,&nbsp;Angela Sloan ,&nbsp;Levi Tamming ,&nbsp;Annabelle Pfeifle ,&nbsp;Caroline Gravel ,&nbsp;Sathya N. Thulasi Raman ,&nbsp;Gary Van Domselaar ,&nbsp;Michael J.W. Johnston ,&nbsp;Lisheng Wang ,&nbsp;Simon Sauve ,&nbsp;Michael Rosu-Myles ,&nbsp;Darwyn Kobasa ,&nbsp;Anh Tran ,&nbsp;Wangxue Chen ,&nbsp;Xu Zhang ,&nbsp;David Safronetz ,&nbsp;Xuguang Li","doi":"10.1016/j.antiviral.2025.106284","DOIUrl":"10.1016/j.antiviral.2025.106284","url":null,"abstract":"<div><div>Influenza A viruses are categorized into two phylogenetic groups (group 1 and group 2) based on the structure of their hemagglutinin (HA) protein. Within group 2, H3N2 poses a particular challenge due to its rapid evolution, limited vaccine efficacy, and association with more severe influenza seasons. Although T cell responses have been extensively studied in the context of vaccine-induced protection, HA stem (HA2)-specific T cell responses have been relatively understudied, especially those related to nasal immunity. To address this, we engineered an adenoviral vector vaccine (Ad-HA2) expressing a consensus hemagglutinin stem sequence, derived through bioinformatic analysis of all H3 strains. The vaccine conferred heterosubtypic protection against lethal challenges with either H3N2 or H7N9, both belonging to group 2 influenza A viruses, with protection lasting at least six months post-vaccination. Notably, the vaccine induced robust HA2-specific humoral and cell-mediated responses in the nasal-associated lymphoid tissue (NALT) of the upper respiratory tract, the first line of immune defense against inhaled pathogens. The vaccine also elicited significant levels of antibodies and T cell responses in the lower respiratory tract and pulmonary immune sites. Furthermore, circulating antibodies in the serum demonstrated effective antibody-dependent cellular cytotoxicity (ADCC) activity. Finally, using a peptide pool matrix screening approach combined with <em>in silico</em> verification, we identified an immunogenic C-terminus region of the HA2 consensus sequence that activated CD4⁺ and CD8⁺ T cells, which warrants further investigation. Collectively, these findings are informative for the design and evaluation of mucosal influenza vaccines targeting the hemagglutinin stem.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106284"},"PeriodicalIF":4.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181936","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":"CCHFV-M based DNA vaccine is highly immunogenic in multiple species and protects against challenge in cynomolgus macaques","authors":"John J. Suschak ,&nbsp;Collin J. Fitzpatrick ,&nbsp;Charles J. Shoemaker ,&nbsp;Joshua D. Shamblin ,&nbsp;Lauren E. White ,&nbsp;Curtis R. Cline ,&nbsp;Christina E. Douglas ,&nbsp;Korey L. Delp ,&nbsp;Trevor L.A. Burt ,&nbsp;Kenise D. Lewis ,&nbsp;Suma Ravulapalli ,&nbsp;Susan Coyne ,&nbsp;Carmen Ledesma-Feliciano ,&nbsp;Gregg Wilson ,&nbsp;Sarah L.W. Norris ,&nbsp;Jennifer L. Scruggs ,&nbsp;Ian Davis ,&nbsp;Keersten M. Ricks ,&nbsp;Christopher P. Stefan ,&nbsp;Scott P. Olshner ,&nbsp;Aura R. Garrison","doi":"10.1016/j.antiviral.2025.106282","DOIUrl":"10.1016/j.antiviral.2025.106282","url":null,"abstract":"<div><div>Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the <em>Nairoviridae</em> family, is the most widely distributed tick-borne virus of medical importance. There are no internationally licensed vaccines, and treatment is limited to supportive care. We previously developed a DNA vaccine expressing the full-length codon-optimized M-segment (CCHFV-M_Afg09), encoding the structural and non-structural viral glycoproteins that protects mice against CCHFV when delivered by intramuscular electroporation (IM-EP). Here, the immunogenicity and protective efficacy of the vaccine delivered by IM-EP was assessed in the non-lethal CCHFV cynomolgus macaque model. The vaccine elicited a significant antibody response to two glycoproteins, the structural G_C and non-structural GP38. CCHFV-M_Afg09 elicited quantifiable T-cell responses directed against the glycoproteins encoded within the M-segment, with anti-G_N immunity reaching significance. Upon intravenous infection with CCHFV, the vaccine protected 5/6 animals against viremia and reduced the pro-inflammatory response compared to sham vaccinated macaques. Numerous macaques also had detectable viral protein and viral RNA in several tissues 28 days post infection. In addition, we determined that an alternative delivery modality, jet injection, was immunogenic in both rabbits and mice, and conferred significant protection in mice. The simplicity and efficacy of disposable syringe needle-free injection system (NFIS) provides a pragmatic approach to advance the CCHF-M DNA vaccine into the clinic. Our M-segment based DNA vaccine elicits both cellular and humoral immunity and significant protection in mice and NHPs, demonstrating for the first time that a vaccine based on the glycoproteins alone is efficacious in the NHP model, which has not previously been shown.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106282"},"PeriodicalIF":4.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063302","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":"Verteporfin is a broad-spectrum inhibitor of arboviruses and influences viral and host-based events","authors":"Carol A. Anderson ,&nbsp;Stephanie V. Trefry ,&nbsp;Michael D. Barrera ,&nbsp;Niloufar Boghdeh ,&nbsp;Sanskruthi Sreepangi ,&nbsp;Lorreta Opoku ,&nbsp;Maria F. Galarza ,&nbsp;Amanda R. Bliss ,&nbsp;Janard L. Bleach ,&nbsp;Farhang Alem ,&nbsp;Elsa Ronzier ,&nbsp;Elaine S. Cerchin ,&nbsp;Christina L. Gardner ,&nbsp;Crystal W. Burke ,&nbsp;Aarthi Narayanan","doi":"10.1016/j.antiviral.2025.106281","DOIUrl":"10.1016/j.antiviral.2025.106281","url":null,"abstract":"<div><div>There is an unmet need for broadly effective therapeutic strategies to address the globally expanding health burden caused by vector-transmitted viruses. Protein-protein interactions involving host and viral proteins are key regulators of a productive viral infection and interruption of such interactions can exert broad-spectrum antiviral outcomes. Verteporfin (VP), a small molecule that is currently approved by the United States Food and Drug Administration (FDA) for the treatment of age-related macular degeneration and a known Yes-associated protein (YAP) inhibitor, was identified as a robust inhibitor of Venezuelan Equine Encephalitis Virus (VEEV) TC-83 strain from a protein-protein interaction inhibitor library. VP demonstrated a cell type independent reduction of viral load with inhibitory mechanism including reduction of nonstructural and structural protein levels. VP treatment also impacted its known target YAP, resulting in reduced expression of total and phosphorylated YAP in virus-infected cells. The <em>in vivo</em> assessment of VP in a lethal infection rodent model demonstrated early promise by increasing survival of infected animals, while also indicating the need for additional improvements in dosing strategy. Assessment of VP-mediated inhibition of other RNA viruses including Old- and New-world alphaviruses, a prototype flavivirus and bunyavirus demonstrated the potential of VP to function as a broad-spectrum inhibitor of vector-transmitted viruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106281"},"PeriodicalIF":4.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063357","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":"Differential effects of antiretroviral HIV integrase inhibitors on vascular cell adhesion molecules","authors":"Ángeles Álvarez-Ribelles ,&nbsp;Sandra Fernández-Rodríguez ,&nbsp;Irene Carrasco-Hernández ,&nbsp;Ana Blas-García ,&nbsp;Víctor Collado-Díaz ,&nbsp;Juan V. Esplugues","doi":"10.1016/j.antiviral.2025.106283","DOIUrl":"10.1016/j.antiviral.2025.106283","url":null,"abstract":"<div><div>Integrase strand transfer inhibitors (INSTIs) have been linked to early cardiovascular (CV) complications. Despite the underlying mechanisms remain unclear, a proinflammatory effect has been suggested. Given the role of adhesion molecules in mediating endothelial interactions with leukocytes and platelets during vascular inflammation and thrombosis, we compared the impact of four INSTIs—dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL), and cabotegravir (CAB)—and the non-nucleoside reverse transcriptase inhibitor doravirine (DOR), which is not associated with excessive CV risk, on adhesion molecule expression. Human blood, platelet-rich plasma, and endothelial cells from umbilical veins of healthy donors were incubated with clinically relevant drug concentrations and the expression of leukocyte, endothelium and platelet adhesion molecules was assessed by flow cytometry. BIC and CAB selectively activated neutrophils and monocytes, as evidenced by increased Mac-1 expression and L-selectin shedding. DTG, BIC, and DOR enhanced ICAM-1 expression on endothelial cells, while DTG and BIC also up-regulated VCAM-1, P-selectin and E-selectin levels. Additionally, DTG and BIC potentiated ADP-induced P-selectin expression in platelets. Overall, BIC produced the most significant pro-inflammatory changes, activating leukocytes, endothelial cells, and platelets; DTG primarily targeted the endothelium and platelets; CAB and DOR specifically activated leukocytes and endothelium, respectively, and RAL had no detectable effect. Our findings reveal distinct immunomodulatory profiles among the different INSTIs in vitro, rather than a class-wide effect. Future studies in patients with HIV will be needed to confirm the proinflammatory effects of DTG, BIC and CAB and to explore their potential implications for CV risk.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106283"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting of the cellular ATM rather than ATR kinase exhibits therapeutic potential during the lumpy skin disease virus infection in vivo and in vitro","authors":"Shanhui Ren ,&nbsp;Haotai Chen ,&nbsp;Shasha Wang ,&nbsp;Zaib Ur Rehman ,&nbsp;Xiaolong Gao ,&nbsp;Xue Yang ,&nbsp;Xiangwei Wang ,&nbsp;Xiangping Yin ,&nbsp;Jianlin Han ,&nbsp;Yuefeng Sun","doi":"10.1016/j.antiviral.2025.106280","DOIUrl":"10.1016/j.antiviral.2025.106280","url":null,"abstract":"<div><div>Due to the lack of timely vaccine prevention and effective drug treatment, lumpy skin disease is increasingly becoming a global epidemic, including in China. There is an urgent need to explore the pathogenic mechanism of lumpy skin disease virus (LSDV) and develop practical therapeutic approaches. The present study provides concrete evidence for the simultaneous induction and activation of nuclear ATM-mediated double-strand break and ATR kinase-dependent single-strand break signaling cascades during LSDV replication in the cytoplasm. Specific drug-inhibitory experiments targeting ATM and ATR kinase activity have showed that LSDV activates the host deoxyribonucleic acid (DNA) damage response (DDR) to facilitate viral replication via ATM-Chk2 rather than the ATR-Chk1 signaling axis <em>in vitro</em>. Meanwhile, animal experiments corroborated the efficacy of an inhibitor drug targeting ATM kinase in decreasing the clinical symptoms of LSDV-infected cattle <em>in vivo</em>. These findings highlight how LSDV exploits the nuclear DDR pathway to enhance replication in the cytoplasmic viral factory, deepening our understanding of virus-host interactions and providing a new target for developing specific antiviral drugs and interventions.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106280"},"PeriodicalIF":4.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020190","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":"Remarkable photodynamic activity of tetra-cationic porphyrins against Vaccinia virus and Monkeypox virus","authors":"Gilneia da Rosa ,&nbsp;Paulo Henrique Hümmelgen Silva ,&nbsp;José Valter Joaquim Silva Júnior ,&nbsp;Micheli Mainardi Pillat ,&nbsp;Bernardo Almeida Iglesias ,&nbsp;Rudi Weiblen ,&nbsp;Eduardo Furtado Flores","doi":"10.1016/j.antiviral.2025.106279","DOIUrl":"10.1016/j.antiviral.2025.106279","url":null,"abstract":"<div><div>In this context, we evaluated the photodynamic effects of four cationic tetra-(pyridyl)porphyrins against Vaccinia virus Western Reserve (VACV WR) and Monkeypox virus (MPXV). The porphyrins were initially analyzed for cytotoxicity to Vero cells by MTT assay and the maximal non-cytotoxic concentrations were used in virucidal assays. For virucidal assays, VACV-WR (107.5 TCID50/mL) and MPXV suspensions (106.97 TCID50/mL) were incubated with porphyrins, exposed (or not) to white light conditions at 45 min. Aliquots of virus suspensions were collected and quantitated, comparing the titers with those of virus suspensions not exposed to porphyrins and/or to light. Porphyrins <strong>4-PtTPyP</strong>, <strong>3-H₂TMeP</strong> and <strong>4-H₂TMeP</strong> exhibited light-dependent activity and completely inactivated VACV-WR and MPXV after 5, 30 and 45 min of light exposure, respectively. In contrast, derivative 3-PtTPyP inactivated the viruses even in the absence of white light exposure, a light-independent virucidal activity. Virucidal assays were performed in the presence/absence of ROS scavengers. Ascorbic acid (AA) was the only capable of completely inhibiting photodynamic inactivation by the three porphyrins. This indicates a type II photodynamic mechanism by singlet oxygen (¹O₂). These results demonstrated photodynamic inactivation of poxviruses by tetra-cationic porphyrins, supporting their potential use - especially <strong>4-PtTPyP</strong> – for virus inactivation in many applications. These results also pave the way for testing porphyrin in PDT of poxvirus-induced cutaneous lesions. In addition, our data validated the use of VACV as a <em>in vitro</em> model for targeted MPXV virucidal testing.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106279"},"PeriodicalIF":4.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004674","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":"Efficient eukaryotic expression and potent antiviral activity of a long-acting recombinant feline interferon-ω2-Fc fusion protein against major feline viruses","authors":"Yuwei Yang ,&nbsp;Hetao Song ,&nbsp;Ke Zhang ,&nbsp;Siyin Wang ,&nbsp;Ya Zhao ,&nbsp;Qiang Zhang ,&nbsp;Meilin Jin","doi":"10.1016/j.antiviral.2025.106272","DOIUrl":"10.1016/j.antiviral.2025.106272","url":null,"abstract":"<div><div>Feline interferon-ω2 (FeIFN-ω2) holds potential as a therapeutic agent against feline viral infections. However, its clinical application is limited by rapid clearance and suboptimal antiviral effectiveness. Thus, in this study, an Fc-fused construct, FeIFN-ω2-Fc, was engineered to improve antiviral potency and pharmacokinetic properties both <em>in vitro</em> and in vivo. Three recombinant constructs—native FeIFN-ω2, FeIFN-ω2-Dimer, and FeIFN-ω2-Fc—were expressed in Chinese Hamster Ovary cells. All showed strong antiviral activity (10^6.74–10^8.42 IU/mg) and effectively activated downstream interferon signaling. Functional assays, including 50 % tissue culture infectious dose assay, quantitative polymerase chain reaction, and immunofluorescence, confirmed their ability to inhibit feline calicivirus (FCV), feline herpesvirus type 1 (FHV-1), and feline parvovirus (FPV). Glycosylation analysis revealed two sites (S102 and T128) in the ω2 domain of FeIFN-ω2-Fc that contributed to its structural stability and functional enhancement. Among the three candidates, FeIFN-ω2-Fc demonstrated the best overall profile, with higher expression levels, simplified purification, and favorable pharmacokinetics. In animal models, it was well tolerated and significantly alleviated clinical symptoms, reduced viral loads, and preserved tissue integrity following FHV-1 infection. Pharmacokinetic studies showed a marked increase in plasma half-life, from 5.80 ± 1.75 h for the native protein to 34.05 ± 6.36 h for the Fc-fused form. Further extension to 40.55 ± 6.61 h was achieved by introducing YTE mutations (S250Y/S252T/T254E) within the Fc region. Based on these findings, a dosing regimen of 4 × 10⁵ IU/kg every other day is proposed, supporting FeIFN-ω2-Fc as a strong candidate for feline antiviral therapy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106272"},"PeriodicalIF":4.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005891","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 determinants of nervous system exposure of adibelivir (IM-250) and related herpes helicase-primase inhibitors across animal species","authors":"Christian Gege,&nbsp;Thomas Hoffmann,&nbsp;Gerald Kleymann","doi":"10.1016/j.antiviral.2025.106271","DOIUrl":"10.1016/j.antiviral.2025.106271","url":null,"abstract":"<div><div>The high incidence and prevalence of herpes infections pose a significant health burden worldwide. Herpes simplex virus infections are the cause of herpes labialis, genital herpes or herpes keratitis and in rare cases life-threatening herpes encephalitis, meningitis or disseminated disease. After primary infection, herpes simplex viruses (HSVes) establish latency in the trigeminal and sacral ganglia and at least 30 % of patients experience clinically manifestant recurrences for life. For effective treatment of these neurotrophic HSVes, adequate drug exposure in the nervous system is essential.</div><div>Here we report the post administration exposure of structurally different helicase-primase inhibitors (HPIs) in plasma, blood, organs and, in particular, the nervous system of animals by HPLC/MS. In diverse animal species, after single or multiple doses of helicase-primase drugs by oral or intravenous administration, only adibelivir (IM-250) achieved concentrations in the nervous system in the range of plasma or blood levels (ratio 0.5 to 4 nervous system/plasma), while other helicase-primase inhibitors with distinct structures, including amenamevir, pritelivir or ABI-5366, showed a low brain/plasma ratio of less than 0.1. The efficient passage of helicase-primase drugs through the blood-brain and blood-nerve barrier is based on their distinct structure and chemical properties. In preclinical studies published so far, adibelivir was efficacious in the herpes encephalitis and neonatal animal model and reduced the reactivation competence of the neuronal latent herpes viral reservoir. Ongoing clinical trials with HPIs will show whether sufficient drug exposure in brain and ganglia will translate into more effective herpes therapies for patients.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106271"},"PeriodicalIF":4.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005816","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}