Monoclonal antibodies are widely used for the treatment of infectious human diseases, including COVID-19. Since the start of the pandemic, eight monoclonal antibodies against SARS-CoV-2 were granted emergency use authorization. The high mutation rate of the SARS-CoV-2 virus has led to the emergence of highly transmissible variants that can evade vaccine-induced immunity. In this study, we generated a panel of murine monoclonal antibodies (mAb) to identify a subset that broadly neutralized SARS-CoV-2 variants and explored whether mucosal administration of such antibodies could protect against infection. Intranasal delivery of XR10, the most promising murine mAb, protected hamsters against infection by Delta variant. We next humanized XR10 mAb using a combination of CDR-grafting and Vernier zones preservation approaches (CRVZ) to create a panel of humanized XR10 variants. We ranked the variants based on their spike binding ability and virus neutralization. Of these, XR10v48 demonstrated the best ability to neutralize SARS-CoV-2 variants and was protective in hamsters when given as a single 50 μg/kg intranasal dose at the time of viral challenge. XR10v48 featured 34 key amino acid residues retained from the murine progenitor. With SARS-CoV-2 escape mutants continuing to emerge this work highlights a potential workflow to generate humanized broadly cross-neutralizing mAb for potential use as a nasal spray for SARS-CoV-2 prophylaxis.
{"title":"SARS-CoV-2 neutralization and protection of hamsters via nasal administration of a humanized neutralizing antibody","authors":"Mikhail Lebedin , Nikolai Petrovsky , Kairat Tabynov , Kaissar Tabynov , Yuri Lebedin","doi":"10.1016/j.antiviral.2025.106235","DOIUrl":"10.1016/j.antiviral.2025.106235","url":null,"abstract":"<div><div>Monoclonal antibodies are widely used for the treatment of infectious human diseases, including COVID-19. Since the start of the pandemic, eight monoclonal antibodies against SARS-CoV-2 were granted emergency use authorization. The high mutation rate of the SARS-CoV-2 virus has led to the emergence of highly transmissible variants that can evade vaccine-induced immunity. In this study, we generated a panel of murine monoclonal antibodies (mAb) to identify a subset that broadly neutralized SARS-CoV-2 variants and explored whether mucosal administration of such antibodies could protect against infection. Intranasal delivery of XR10, the most promising murine mAb, protected hamsters against infection by Delta variant. We next humanized XR10 mAb using a combination of CDR-grafting and Vernier zones preservation approaches (CRVZ) to create a panel of humanized XR10 variants. We ranked the variants based on their spike binding ability and virus neutralization. Of these, XR10v48 demonstrated the best ability to neutralize SARS-CoV-2 variants and was protective in hamsters when given as a single 50 μg/kg intranasal dose at the time of viral challenge. XR10v48 featured 34 key amino acid residues retained from the murine progenitor. With SARS-CoV-2 escape mutants continuing to emerge this work highlights a potential workflow to generate humanized broadly cross-neutralizing mAb for potential use as a nasal spray for SARS-CoV-2 prophylaxis.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106235"},"PeriodicalIF":4.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616059","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}
Understanding the evolution of broadly neutralizing antibody (bNAb) activity in people living with HIV is crucial for vaccine design and immunization strategies. It has been proposed that antibody cross-reactive activity is associated with lower CD4+ T cell counts during people living with HIV, but the underlying mechanisms remain unclear. To further explore the correlation between antibody reactivity and CD4+ T cell counts, we recruited people living with HIV with varying CD4+ T cell counts: (i) CD4+ T cell ≤50 cells/μL, (ii) 50 cells/μL < CD4+ T cell ≤200 cells/μL, (iii) 200 cells/μL < CD4+ T cell ≤500 cells/μL, (iv) 500 cells/μL < CD4+ T cell. We assessed the antigen-specific antibodies in serum using SOSIP.664 trimers from four different subtypes. Immune repertoire sequencing was used to characterize the B cell receptor (BCR) repertoire of these individuals. The evaluation of antigen-specific antibodies with different SOSIP.664 trimers showed enhanced reactivity in individuals with low CD4+ T cell counts compared to those with high/normal CD4+ T cell counts. Analysis of antibody gene repertoires through BCR high throughput sequencing revealed an increased proportion of IgG with heavy chain complementarity-determining region 3 (CDRH3) loops exceeding 20 amino acids in individuals with CD4+ T cell counts below 50 cells/μL. Notably, the IGHV1-46 and IGHV4-34 germlines, which are suggestive of most polyreactive B cells, were preferentially used in individuals with low CD4+ T cell counts. These results suggest that limited engagement of CD4+ T cells could facilitate the survival of aberrant B cell repertoire with long CDRH3 regions.
{"title":"Decreased CD4+ T cell counts drive aberrant B cell repertoire alterations in people living with HIV","authors":"Lina Huang , Xiangyu Zhang , Yu Shi , Rishen Liang , Qianqian Chen , Jing Yang , Xiaoni Zhang , Anning Fang , Qian Zhang , Chengchao Ding , Jiabin Wu , Jianjun Wu , Yong Gao","doi":"10.1016/j.antiviral.2025.106236","DOIUrl":"10.1016/j.antiviral.2025.106236","url":null,"abstract":"<div><div>Understanding the evolution of broadly neutralizing antibody (bNAb) activity in people living with HIV is crucial for vaccine design and immunization strategies. It has been proposed that antibody cross-reactive activity is associated with lower CD4<sup>+</sup> T cell counts during people living with HIV, but the underlying mechanisms remain unclear. To further explore the correlation between antibody reactivity and CD4<sup>+</sup> T cell counts, we recruited people living with HIV with varying CD4<sup>+</sup> T cell counts: (i) CD4<sup>+</sup> T cell ≤50 cells/μL, (ii) 50 cells/μL < CD4<sup>+</sup> T cell ≤200 cells/μL, (iii) 200 cells/μL < CD4<sup>+</sup> T cell ≤500 cells/μL, (iv) 500 cells/μL < CD4<sup>+</sup> T cell. We assessed the antigen-specific antibodies in serum using SOSIP.664 trimers from four different subtypes. Immune repertoire sequencing was used to characterize the B cell receptor (BCR) repertoire of these individuals. The evaluation of antigen-specific antibodies with different SOSIP.664 trimers showed enhanced reactivity in individuals with low CD4<sup>+</sup> T cell counts compared to those with high/normal CD4<sup>+</sup> T cell counts. Analysis of antibody gene repertoires through BCR high throughput sequencing revealed an increased proportion of IgG with heavy chain complementarity-determining region 3 (CDRH3) loops exceeding 20 amino acids in individuals with CD4<sup>+</sup> T cell counts below 50 cells/μL. Notably, the IGHV1-46 and IGHV4-34 germlines, which are suggestive of most polyreactive B cells, were preferentially used in individuals with low CD4<sup>+</sup> T cell counts. These results suggest that limited engagement of CD4<sup>+</sup> T cells could facilitate the survival of aberrant B cell repertoire with long CDRH3 regions.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106236"},"PeriodicalIF":4.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607247","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}
Pub Date : 2025-07-05DOI: 10.1016/j.antiviral.2025.106234
Yi-Fan Guo , Yihui Rong , Yan-Ping Chen , Song Yang , Guangde Zhou , Xiao-Xia Niu , Xiao-Huan Wu , Yue-Ran Liu , Wen-Jing Zhang , Le Li , Yan Liu , Wen-Chang Wang , Xu-Yang Li , Chun-Yan Wang , Wucai Yang , Chang Guo , Lin Tan , Fu-Sheng Wang , Dong Ji
Whether patients aged ≤30 years with chronic hepatitis B (CHB) and normal alanine transaminase (ALT) levels (<40 U/L) should receive antiviral therapy is controversial. In this study, we aimed to identify high-risk factors of significant hepatic damage (SHD) and established a scoring system to guide the decision to administer antiviral treatment. Eligible patients who underwent a liver biopsy were retrospectively screened and randomly assigned to either a training or validation set. Hepatic fibrosis (S0-4) and inflammation (G0-4) were assessed using the Scheuer scoring system. The independent risk factors associated with SHD (≥G2/S2) were identified using univariable and multivariable logistic regression analyses, and a new scoring system based on these factors was established. Among the 883 enrolled patients, 548 (62.1 %) were male, and 250 (28.5 %) presented with SHD. ALT, platelet count, HBV DNA, and liver stiffness measurement were identified as independent risk factors. A new scoring model based on these factors, named APLB, was developed. The area under the curve of APLB was 0.731 (95 % confidence interval, 0.695–0.764), which was significantly higher than those of the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) index. An APLB score <6 points ruled out SHD with 80.2 % sensitivity, while scores >12 points diagnosed SHD with 97.5 % specificity. In conclusion, the APLB scoring model demonstrated superior diagnostic performance compared with the APRI and the FIB-4 index, and it has the potential to guide the decision to initiate antiviral therapy in this patient group.
{"title":"Assessment of significant hepatic damage in young patients with chronic hepatitis B to initiate the antiviral treatment: The APLB score","authors":"Yi-Fan Guo , Yihui Rong , Yan-Ping Chen , Song Yang , Guangde Zhou , Xiao-Xia Niu , Xiao-Huan Wu , Yue-Ran Liu , Wen-Jing Zhang , Le Li , Yan Liu , Wen-Chang Wang , Xu-Yang Li , Chun-Yan Wang , Wucai Yang , Chang Guo , Lin Tan , Fu-Sheng Wang , Dong Ji","doi":"10.1016/j.antiviral.2025.106234","DOIUrl":"10.1016/j.antiviral.2025.106234","url":null,"abstract":"<div><div>Whether patients aged ≤30 years with chronic hepatitis B (CHB) and normal alanine transaminase (ALT) levels (<40 U/L) should receive antiviral therapy is controversial. In this study, we aimed to identify high-risk factors of significant hepatic damage (SHD) and established a scoring system to guide the decision to administer antiviral treatment. Eligible patients who underwent a liver biopsy were retrospectively screened and randomly assigned to either a training or validation set. Hepatic fibrosis (S0-4) and inflammation (G0-4) were assessed using the Scheuer scoring system. The independent risk factors associated with SHD (≥G2/S2) were identified using univariable and multivariable logistic regression analyses, and a new scoring system based on these factors was established. Among the 883 enrolled patients, 548 (62.1 %) were male, and 250 (28.5 %) presented with SHD. ALT, platelet count, HBV DNA, and liver stiffness measurement were identified as independent risk factors. A new scoring model based on these factors, named APLB, was developed. The area under the curve of APLB was 0.731 (95 % confidence interval, 0.695–0.764), which was significantly higher than those of the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) index. An APLB score <6 points ruled out SHD with 80.2 % sensitivity, while scores >12 points diagnosed SHD with 97.5 % specificity. In conclusion, the APLB scoring model demonstrated superior diagnostic performance compared with the APRI and the FIB-4 index, and it has the potential to guide the decision to initiate antiviral therapy in this patient group.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106234"},"PeriodicalIF":4.5,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572844","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}
Pub Date : 2025-07-05DOI: 10.1016/j.antiviral.2025.106233
Lance A Mulder , Renata Vieira da Sá , Joep Korsten , Eline Freeze , Amber J. Schotting , Gerrit Koen , Richard Molenkamp , Jeroen Van Kampen , Marion Cornelissen , Fokla Zorgdrager , Katja C Wolthers , Dasja Pajkrt , Adithya Sridhar , Carlemi Calitz
Human cytomegalovirus (CMV) infections can cause severe neurological complications, particularly in newborns and immunocompromised patients. Children affected with congenital CMV infection may develop long-term neurological damage and intellectual disabilities. Currently, postnatal antiviral therapies are limited and there are no prenatal options available. Research on antivirals against congenital CMV infections is, at least partly, restricted due to the lack of physiologically relevant models and the use of lab-adapted CMV strains with limited clinical relevance. In this study, we evaluated the toxicity and antiviral efficacy of three FDA-approved anti-CMV drugs against two CMV strains, a clinical and a lab-adapted strain, using two human induced pluripotent stem cell (iPSC-)derived central nervous system models, viz. neural progenitor cells (NPCs) and dorsal forebrain regionalized neural organoids (RNOs). We found iPSC line-dependent differences in antiviral toxicity. We observed that antiviral treatment restored NPCs and RNOs gene expression after CMV infection and reduced CMV copy numbers. Infection of NPCs and RNOs with the clinical CMV strain, but not with the lab-adapted strain, led to an impaired expression of cortical development markers. Our findings highlight the value of using physiologically relevant human models and clinical CMV strains to understand the neuropathogenesis of congenital CMV and to test therapeutic strategies.
{"title":"Effect of antivirals on clinical and lab-adapted human cytomegalovirus strains using induced pluripotent stem cell-derived human neural models","authors":"Lance A Mulder , Renata Vieira da Sá , Joep Korsten , Eline Freeze , Amber J. Schotting , Gerrit Koen , Richard Molenkamp , Jeroen Van Kampen , Marion Cornelissen , Fokla Zorgdrager , Katja C Wolthers , Dasja Pajkrt , Adithya Sridhar , Carlemi Calitz","doi":"10.1016/j.antiviral.2025.106233","DOIUrl":"10.1016/j.antiviral.2025.106233","url":null,"abstract":"<div><div>Human cytomegalovirus (CMV) infections can cause severe neurological complications, particularly in newborns and immunocompromised patients. Children affected with congenital CMV infection may develop long-term neurological damage and intellectual disabilities. Currently, postnatal antiviral therapies are limited and there are no prenatal options available. Research on antivirals against congenital CMV infections is, at least partly, restricted due to the lack of physiologically relevant models and the use of lab-adapted CMV strains with limited clinical relevance. In this study, we evaluated the toxicity and antiviral efficacy of three FDA-approved anti-CMV drugs against two CMV strains, a clinical and a lab-adapted strain, using two human induced pluripotent stem cell (iPSC-)derived central nervous system models, <em>viz.</em> neural progenitor cells (NPCs) and dorsal forebrain regionalized neural organoids (RNOs). We found iPSC line-dependent differences in antiviral toxicity. We observed that antiviral treatment restored NPCs and RNOs gene expression after CMV infection and reduced CMV copy numbers. Infection of NPCs and RNOs with the clinical CMV strain, but not with the lab-adapted strain, led to an impaired expression of cortical development markers. Our findings highlight the value of using physiologically relevant human models and clinical CMV strains to understand the neuropathogenesis of congenital CMV and to test therapeutic strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106233"},"PeriodicalIF":4.5,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574740","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}
Pub Date : 2025-07-03DOI: 10.1016/j.antiviral.2025.106222
Robert Jordan , Nancie M. Archin , Valeria Cagno , Joy Y. Feng , Haitao Guo , Lara J. Herrero , Zlatko Janeba , Nicholas A. Meanwell , Jennifer Moffat , Johan Neyts , Joana Rocha-Pereira , Kathie L. Seley-Radtke , Timothy P. Sheahan , Jessica R. Spengler , Stephen R. Welch , Xuping Xie , Hovakim Zakaryan , Luis M. Schang , David Durantel
The 38th International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), took place March 17–21, 2025 in Las Vegas, Nevada, USA. The annual meeting brought together leading scientists from across academia, industry, and government to present the latest advances in antiviral research. Topics included discovery and development of novel antiviral agents, innovative therapeutic approaches, vaccine technologies, host-targeted strategies, and responses to emerging and re-emerging viral threats. ICAR 2025 featured keynote talks, short oral presentations, poster sessions and special sessions to encourage discussions between attendees and foster interdisciplinary collaboration. Several events were held to support the next generation of antiviral researchers, including dedicated sessions and networking opportunities focused on mentorship and career development for students, postdoctoral fellows, and early-career scientists. Importantly, ISAR continues to serve as a cornerstone for international collaboration and innovation in antiviral science, and the society is eager to continue these efforts at the 39th ICAR, to be held in Prague, Czech Republic, from April 27–May 1, 2026.
{"title":"Meeting report: 38th international conference on antiviral research in Las Vegas, United States of America, March 17–21, 2025","authors":"Robert Jordan , Nancie M. Archin , Valeria Cagno , Joy Y. Feng , Haitao Guo , Lara J. Herrero , Zlatko Janeba , Nicholas A. Meanwell , Jennifer Moffat , Johan Neyts , Joana Rocha-Pereira , Kathie L. Seley-Radtke , Timothy P. Sheahan , Jessica R. Spengler , Stephen R. Welch , Xuping Xie , Hovakim Zakaryan , Luis M. Schang , David Durantel","doi":"10.1016/j.antiviral.2025.106222","DOIUrl":"10.1016/j.antiviral.2025.106222","url":null,"abstract":"<div><div>The 38th International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), took place March 17–21, 2025 in Las Vegas, Nevada, USA. The annual meeting brought together leading scientists from across academia, industry, and government to present the latest advances in antiviral research. Topics included discovery and development of novel antiviral agents, innovative therapeutic approaches, vaccine technologies, host-targeted strategies, and responses to emerging and re-emerging viral threats. ICAR 2025 featured keynote talks, short oral presentations, poster sessions and special sessions to encourage discussions between attendees and foster interdisciplinary collaboration. Several events were held to support the next generation of antiviral researchers, including dedicated sessions and networking opportunities focused on mentorship and career development for students, postdoctoral fellows, and early-career scientists. Importantly, ISAR continues to serve as a cornerstone for international collaboration and innovation in antiviral science, and the society is eager to continue these efforts at the 39th ICAR, to be held in Prague, Czech Republic, from April 27–May 1, 2026.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106222"},"PeriodicalIF":4.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566944","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}
Pub Date : 2025-07-01DOI: 10.1016/j.antiviral.2025.106223
Barnault Romain , Vicente-Navarro Inés , Lotteau Vincent , Durantel David , Ramière Christophe
As intracellular organisms, viruses exploit host metabolism to replicate and propagate. The farnesoid X receptor alpha (FXRα) is a bile acid-activated nuclear receptor that regulates bile acid, glucose and lipid metabolism, as well as inflammation and immunity. Since its discovery in 1995, numerous ligands have been developed to treat metabolism-related syndromes. More recently, FXRα has been shown to modulate the life cycle of various viruses that infect human. This review provides a comprehensive summary of the literature regarding the effect of FXRα agonism in viral infections caused by hepatotropic viruses, enteric viruses and other viral pathogens. Rather than acting through a single antiviral mechanism, FXRα has been reported to influence many steps of viral replication, including entry, transcription and particle secretion. The established safety profiles of FXRα agonists and their clinical use for other pathologies could pave the way for their re-purposing as broad-spectrum antivirals.
{"title":"Farnesoid X receptor agonists as broad-acting antivirals: Evidence from hepatitis viruses and beyond?","authors":"Barnault Romain , Vicente-Navarro Inés , Lotteau Vincent , Durantel David , Ramière Christophe","doi":"10.1016/j.antiviral.2025.106223","DOIUrl":"10.1016/j.antiviral.2025.106223","url":null,"abstract":"<div><div>As intracellular organisms, viruses exploit host metabolism to replicate and propagate. The farnesoid X receptor alpha (FXRα) is a bile acid-activated nuclear receptor that regulates bile acid, glucose and lipid metabolism, as well as inflammation and immunity. Since its discovery in 1995, numerous ligands have been developed to treat metabolism-related syndromes. More recently, FXRα has been shown to modulate the life cycle of various viruses that infect human. This review provides a comprehensive summary of the literature regarding the effect of FXRα agonism in viral infections caused by hepatotropic viruses, enteric viruses and other viral pathogens. Rather than acting through a single antiviral mechanism, FXRα has been reported to influence many steps of viral replication, including entry, transcription and particle secretion. The established safety profiles of FXRα agonists and their clinical use for other pathologies could pave the way for their re-purposing as broad-spectrum antivirals.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106223"},"PeriodicalIF":4.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558903","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}
Pub Date : 2025-06-26DOI: 10.1016/j.antiviral.2025.106221
Ann E. Tollefson , Anna Cline-Smith , Vincent Roy , Luigi A. Agrofoglio , Getahun Abate , Franck Gallardo , Karoly Toth
LAVR-289, a newly described acyclic nucleoside phosphonate prodrug, has previously shown in vitro efficacy against adenovirus (HAdV) species B, C, D, E, and F with EC50 values of 100 nM to 1.2 μM. The compound was efficacious prophylactically against systemic HAdV infection in immunosuppressed Syrian hamsters. Here, we present further, more detailed data on its efficacy against HAdV. We tested the two enantiomers at chiral phosphorus center (Sp and Rp) of LAVR-289 and found that both stereoisomers were equally efficacious against HAdV-C5 and -C6 infecting human foreskin fibroblast primary cells in vitro, indicating that the racemic mixture of the compound could be used as a drug. Following these favorable in vitro results, the antiviral activity of racemic LAVR-289 was evaluated in the immunosuppressed Syrian hamster model, in which the hamsters were challenged with the intravenous LD90 dose of HAdV-C6. Prophylactic administration of LAVR-289 completely prevented mortality at doses of 24 mg/kg p.o. q.d. or higher. At the efficacious dose levels, it significantly inhibited virus replication in the liver and mitigated HAdV-C6-induced liver damage. As prophylactic administration may not be advisable in a clinical setting, we delayed the administration of LAVR-289 and showed that the compound prevented mortality and significantly reduced morbidity even when the drug was withheld for 3 days post challenge. Based on these results, we believe that these data demonstrate in vitro and in vivo potency of LAVR-289 against HAdVs and support its continued development.
{"title":"LAVR-289, a broad-spectrum antiviral, protects immunosuppressed Syrian hamsters against lethal adenovirus challenge","authors":"Ann E. Tollefson , Anna Cline-Smith , Vincent Roy , Luigi A. Agrofoglio , Getahun Abate , Franck Gallardo , Karoly Toth","doi":"10.1016/j.antiviral.2025.106221","DOIUrl":"10.1016/j.antiviral.2025.106221","url":null,"abstract":"<div><div>LAVR-289, a newly described acyclic nucleoside phosphonate prodrug, has previously shown <em>in vitro</em> efficacy against adenovirus (HAdV) species B, C, D, E, and F with EC<sub>50</sub> values of 100 nM to 1.2 μM. The compound was efficacious prophylactically against systemic HAdV infection in immunosuppressed Syrian hamsters. Here, we present further, more detailed data on its efficacy against HAdV. We tested the two enantiomers at chiral phosphorus center (<em>Sp</em> and <em>Rp</em>) of LAVR-289 and found that both stereoisomers were equally efficacious against HAdV-C5 and -C6 infecting human foreskin fibroblast primary cells <em>in vitro</em>, indicating that the racemic mixture of the compound could be used as a drug. Following these favorable <em>in vitro</em> results, the antiviral activity of racemic LAVR-289 was evaluated in the immunosuppressed Syrian hamster model, in which the hamsters were challenged with the intravenous LD<sub>90</sub> dose of HAdV-C6. Prophylactic administration of LAVR-289 completely prevented mortality at doses of 24 mg/kg p.o. q.d. or higher. At the efficacious dose levels, it significantly inhibited virus replication in the liver and mitigated HAdV-C6-induced liver damage. As prophylactic administration may not be advisable in a clinical setting, we delayed the administration of LAVR-289 and showed that the compound prevented mortality and significantly reduced morbidity even when the drug was withheld for 3 days post challenge. Based on these results, we believe that these data demonstrate <em>in vitro</em> and <em>in vivo</em> potency of LAVR-289 against HAdVs and support its continued development.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106221"},"PeriodicalIF":4.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517076","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}
Pub Date : 2025-06-24DOI: 10.1016/j.antiviral.2025.106220
Shengchen Bai , Huiru Liang , Weihao Jiang , Limei Xu , Bin Liu , Tengfei Zhou , Baoying Chen , Ruochen Xu , Zhijun Bai , Min Liu
Approximately 390 million individuals globally are infected with dengue virus annually. Notably, no specific therapeutic strategy has been clinically approved for dengue fever to date. In this study, molecular docking screening against the methyltransferase (MTase) domain of the dengue virus (DENV) NS5 protein unveiled hypaphorine as a high-affinity ligand, with calculated binding energies of −6.657 kcal/mol (DENV2) and −6.663 kcal/mol (DENV3). This computational prediction was subsequently validated via cellular thermal shift assay (CETSA) and surface plasmon resonance imaging (SPRi), collectively demonstrating direct target engagement with a dissociation constant (KD) of 2.19 × 10−9 M. Functional characterization revealed that hypaphorine exhibited concentration-dependent inhibition of MTase enzymatic activity (IC50 = 29.9 μM). In antiviral assays, hypaphorine displayed dose-dependent suppression of viral replication in both BHK-21 (IC50 = 18.85 μM) and Huh-7 cells (IC50 = 15.7 μM), while maintaining low cytotoxicity (CC50 = 605.8 μM and 617.3 μM, respectively). Time-course analyses indicated maximal antiviral efficacy when hypaphorine was administered either pre- or post-infection (<24 hpi), which is consistent with the role of MTase in viral RNA capping during successive rounds of virus replication. The reduction in viral titer was found to correlate with MTase inhibition, thereby establishing a clear structure-activity relationship. These findings systematically characterize hypaphorine as a first-in-class natural MTase inhibitor, highlighting the utility of structure-guided approaches in anti-flaviviral drug discovery.
{"title":"Identifying hypaphorine as a novel antiviral compound against dengue virus","authors":"Shengchen Bai , Huiru Liang , Weihao Jiang , Limei Xu , Bin Liu , Tengfei Zhou , Baoying Chen , Ruochen Xu , Zhijun Bai , Min Liu","doi":"10.1016/j.antiviral.2025.106220","DOIUrl":"10.1016/j.antiviral.2025.106220","url":null,"abstract":"<div><div>Approximately 390 million individuals globally are infected with dengue virus annually. Notably, no specific therapeutic strategy has been clinically approved for dengue fever to date. In this study, molecular docking screening against the methyltransferase (MTase) domain of the dengue virus (DENV) NS5 protein unveiled hypaphorine as a high-affinity ligand, with calculated binding energies of −6.657 kcal/mol (DENV2) and −6.663 kcal/mol (DENV3). This computational prediction was subsequently validated via cellular thermal shift assay (CETSA) and surface plasmon resonance imaging (SPRi), collectively demonstrating direct target engagement with a dissociation constant (KD) of 2.19 × 10<sup>−9</sup> M. Functional characterization revealed that hypaphorine exhibited concentration-dependent inhibition of MTase enzymatic activity (IC<sub>50</sub> = 29.9 μM). In antiviral assays, hypaphorine displayed dose-dependent suppression of viral replication in both BHK-21 (IC<sub>50</sub> = 18.85 μM) and Huh-7 cells (IC<sub>50</sub> = 15.7 μM), while maintaining low cytotoxicity (CC<sub>50</sub> = 605.8 μM and 617.3 μM, respectively). Time-course analyses indicated maximal antiviral efficacy when hypaphorine was administered either pre- or post-infection (<24 hpi), which is consistent with the role of MTase in viral RNA capping during successive rounds of virus replication. The reduction in viral titer was found to correlate with MTase inhibition, thereby establishing a clear structure-activity relationship. These findings systematically characterize hypaphorine as a first-in-class natural MTase inhibitor, highlighting the utility of structure-guided approaches in anti-flaviviral drug discovery.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106220"},"PeriodicalIF":4.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480346","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}
Pub Date : 2025-06-24DOI: 10.1016/j.antiviral.2025.106217
Saira Hussain , Adam Meijer , Elena A. Govorkova , Clyde Dapat , Larisa V. Gubareva , Ian G. Barr , Sook Kwan Brown , Rod S. Daniels , Seiichiro Fujisaki , Monica Galiano , Weijuan Huang , Rebecca J. Kondor , Angie Lackenby , Nicola Lewis , Janice Lo , Ha T. Nguyen , Mira C. Patel , Dmitriy Pereyaslov , Aine Rattigan , Magdi Samaan , Emi Takashita
Antiviral susceptibility of influenza viruses is monitored by the World Health Organization Global Influenza Surveillance and Response System. This study describes a global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs, oseltamivir, zanamivir, peramivir, laninamivir) and the cap-dependent endonuclease inhibitor (CENI, baloxavir) for three periods (May to May for 2020–2021, 2021–2022 and 2022–2023). In particular, global influenza activity declined significantly in 2020–2021 and 2021–2022 when compared to the pre-pandemic period of COVID-19. Combined phenotypic and NA sequence-based analysis revealed that the global frequency of seasonal influenza viruses with reduced or highly reduced inhibition (RI/HRI) by NAIs remained low, 0.09% (2/2224), 0.12% (27/23465) and 0.23% (124/53917) for 2020–2021, 2021–2022 and 2022–2023, respectively. As in previous years, NA-H275Y in A(H1N1)pdm09 viruses was the most frequent substitution causing HRI by oseltamivir and peramivir. Sequence-based analysis of polymerase acidic (PA) protein supplemented with phenotypic testing revealed low global frequencies of seasonal influenza viruses with reduced susceptibility (RS) to baloxavir, 0.07% (1/1376), 0.05% (9/18380) and 0.12% (48/39945) for 2020–2021, 2021–2022 and 2022–2023, respectively; commonly associated substitutions were PA-I38T/M/L. In Japan, the rate was 3.3% (16/488) during 2022–2023, with 11 A(H3N2) viruses having PA-I38T/M substitutions. For zoonotic viruses, 2.7% (3/111) contained substitutions, one each NA-H275Y, NA-S247N and NA-N295S, associated with RI/HRI NAI phenotypes, and none contained PA substitutions associated with RS to baloxavir. In conclusion, the great majority of seasonal and zoonotic influenza viruses remained susceptible to NAIs and CENI baloxavir.
{"title":"Global update on the susceptibilities of influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2020–2023","authors":"Saira Hussain , Adam Meijer , Elena A. Govorkova , Clyde Dapat , Larisa V. Gubareva , Ian G. Barr , Sook Kwan Brown , Rod S. Daniels , Seiichiro Fujisaki , Monica Galiano , Weijuan Huang , Rebecca J. Kondor , Angie Lackenby , Nicola Lewis , Janice Lo , Ha T. Nguyen , Mira C. Patel , Dmitriy Pereyaslov , Aine Rattigan , Magdi Samaan , Emi Takashita","doi":"10.1016/j.antiviral.2025.106217","DOIUrl":"10.1016/j.antiviral.2025.106217","url":null,"abstract":"<div><div>Antiviral susceptibility of influenza viruses is monitored by the World Health Organization Global Influenza Surveillance and Response System. This study describes a global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs, oseltamivir, zanamivir, peramivir, laninamivir) and the cap-dependent endonuclease inhibitor (CENI, baloxavir) for three periods (May to May for 2020–2021, 2021–2022 and 2022–2023). In particular, global influenza activity declined significantly in 2020–2021 and 2021–2022 when compared to the pre-pandemic period of COVID-19. Combined phenotypic and NA sequence-based analysis revealed that the global frequency of seasonal influenza viruses with reduced or highly reduced inhibition (RI/HRI) by NAIs remained low, 0.09% (2/2224), 0.12% (27/23465) and 0.23% (124/53917) for 2020–2021, 2021–2022 and 2022–2023, respectively. As in previous years, NA-H275Y in A(H1N1)pdm09 viruses was the most frequent substitution causing HRI by oseltamivir and peramivir. Sequence-based analysis of polymerase acidic (PA) protein supplemented with phenotypic testing revealed low global frequencies of seasonal influenza viruses with reduced susceptibility (RS) to baloxavir, 0.07% (1/1376), 0.05% (9/18380) and 0.12% (48/39945) for 2020–2021, 2021–2022 and 2022–2023, respectively; commonly associated substitutions were PA-I38T/M/L. In Japan, the rate was 3.3% (16/488) during 2022–2023, with 11 A(H3N2) viruses having PA-I38T/M substitutions. For zoonotic viruses, 2.7% (3/111) contained substitutions, one each NA-H275Y, NA-S247N and NA-N295S, associated with RI/HRI NAI phenotypes, and none contained PA substitutions associated with RS to baloxavir. In conclusion, the great majority of seasonal and zoonotic influenza viruses remained susceptible to NAIs and CENI baloxavir.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106217"},"PeriodicalIF":4.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504680","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}
Pub Date : 2025-06-23DOI: 10.1016/j.antiviral.2025.106219
Jin Hong, Vivek K. Rajwanshi
In this review, we provide a historical and current guide of recent advances in the development of ASOs either targeting viruses directly, or indirectly through modulation of host factors. Although preclinical and discovery assets are mentioned in this review, more extensive coverage is given to clinical stage assets. Most of these clinical assets are currently concentrated in the fight to eradicate hepatitis B virus (HBV), and hepatitis C virus (HCV). Progresses have also been made in extrahepatic delivery of oligonucleotides and the possibility of treating respiratory virus infections in lungs with ASOs would be feasible.
{"title":"Antisense oligonucleotides as drugs with both direct and indirect antiviral actions","authors":"Jin Hong, Vivek K. Rajwanshi","doi":"10.1016/j.antiviral.2025.106219","DOIUrl":"10.1016/j.antiviral.2025.106219","url":null,"abstract":"<div><div>In this review, we provide a historical and current guide of recent advances in the development of ASOs either targeting viruses directly, or indirectly through modulation of host factors. Although preclinical and discovery assets are mentioned in this review, more extensive coverage is given to clinical stage assets. Most of these clinical assets are currently concentrated in the fight to eradicate hepatitis B virus (HBV), and hepatitis C virus (HCV). Progresses have also been made in extrahepatic delivery of oligonucleotides and the possibility of treating respiratory virus infections in lungs with ASOs would be feasible.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"240 ","pages":"Article 106219"},"PeriodicalIF":4.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493784","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}
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