Antiviral research最新文献

{"title":"Understanding HBV immunopathogenesis to inform future immune-based therapies.","authors":"Margaux Bossis, Phuong-Ha Le, Tarik Asselah, Thomas F Baumert, Pierre Tonnerre","doi":"10.1016/j.antiviral.2026.106424","DOIUrl":"https://doi.org/10.1016/j.antiviral.2026.106424","url":null,"abstract":"<p><p>Chronic hepatitis B virus (HBV) infection remains a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, with more than 250 million people living with chronic infection despite effective prophylactic vaccination. While current treatments provide durable suppression of viral replication and reduce liver-related complications, they rarely achieve functional cure, defined as sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation. Viral persistence is maintained by intrahepatic covalently closed circular DNA and HBV DNA integration, which sustain antigen production and contribute to immune dysfunction. This review summarizes current understanding of HBV immunopathogenesis across acute resolution and chronicity, emphasizing the compartmentalized and tolerogenic liver microenvironment, impaired innate sensing, and progressive dysfunction of HBV-specific B- and T-cell responses, including exhaustion phenotypes shaped by antigen specificity and intrahepatic priming. We also discuss immune correlates associated with functional cure, including partial restoration of polyfunctional HBV-specific T cells and intrahepatic immune remodeling. Finally, we discuss human clinical trials of immune-based therapies highlighting emerging combination strategies designed to couple antigen reduction with immune restauration, defined as the recovery of functional HBV-specific antiviral responses. Collectively, preclinical and clinical data suggest that achieving durable off-treatment control will likely require approaches that address both viral replication, antigen burden and HBV-specific immune responses.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106424"},"PeriodicalIF":4.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832857","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":"Efficacy of an Fc-silent antibody targeting the apical domain of human transferrin receptor 1 in transgenic mouse models of Junín virus infection.","authors":"Minghao Li, Samantha R Wasson, Tracy R Daniels-Wells, Jonna B Westover, Pierre V Candelaria, Kevin W Bailey, Manuel L Penichet, Brian B Gowen","doi":"10.1016/j.antiviral.2026.106423","DOIUrl":"https://doi.org/10.1016/j.antiviral.2026.106423","url":null,"abstract":"<p><p>Several New World mammarenaviruses (NWMs), including Junín virus (JUNV), can cause a severe, potentially fatal hemorrhagic fever (HF) syndrome. In the absence of FDA-approved vaccines or antivirals, there is an urgent need to develop broadly active countermeasures against these viral infections. Cellular entry by all pathogenic NWMs is mediated by transferrin receptor 1 (TfR1). Here, we report on the pharmacokinetics (PK) and antiviral activity of a mouse/human chimeric antibody, targeting the apical domain of human TfR1 and lacking effector functions (ch128.1/IgG1 Fc-silent) in two transgenic mouse models of JUNV infection. Assessment of tolerability and PK in human TfR1 knock-in/mouse TfR1 knock-out mice (huTfR1 Tg mice) demonstrated that ch128.1/IgG1 Fc-silent (FcS) was well-tolerated at doses up to 800 μg, and that once-daily dosing may be the most effective regimen for achieving optimal therapeutic benefit. Prophylactic and post-infection intervention efficacy studies employing once-daily antibody treatments in huTfR1 Tg mice challenged with JUNV revealed significant protection against mortality, even when treatment was delayed until 5 days post-infection. In mice with TfR1 containing only the apical domain of the human receptor (huApTfR1 Tg mice), the ch128.1/IgG1 FcS treatment trended toward increased survival and significantly reduced weight loss following JUNV challenge. The antibody treatments also significantly decreased infectious JUNV titers in target organs (liver and spleen) in the more physiologically relevant huApTfR1 Tg mouse model. Taken together, effective treatment of advanced JUNV infection in two transgenic mouse models with ch128.1/IgG1 FcS antibody supports the development of a humanized version of this antibody for clinical application.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106423"},"PeriodicalIF":4.0,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810088","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":"Human intestinal organoid-derived epithelium reveals donor-dependent antiviral responses to therapeutics against enteric picornaviruses.","authors":"Joep Korsten, Carlemi Calitz, Ikrame Aknouch, Nina Johannesson, Inés García-Rodríguez, Emma Schram, Dasja Pajkrt, Adithya Sridhar, Katja Wolthers","doi":"10.1016/j.antiviral.2026.106422","DOIUrl":"https://doi.org/10.1016/j.antiviral.2026.106422","url":null,"abstract":"<p><p>Human picornavirus infections remain without approved antiviral therapies. Antiviral testing performed in immortalised cell lines often fails to predict antiviral efficacy in vivo and subsequently clinical outcomes. Here, we assessed how antiviral responses to clinically approved compounds differ between immortalised intestinal cell lines and a physiologically relevant human intestinal organoid-derived epithelium (HIE) model. Posaconazole, itraconazole, ribavirin, remdesivir, and pocapavir, compounds with reported anti-picornaviral activity in cell lines, were evaluated against enterovirus A71 (EV-A71) and human parechovirus 1 (HPeV-1) in Caco-2 and HT-29 cell lines, and human foetal HIE monolayers from multiple donors. Remdesivir consistently inhibited EV-A71 replication in Caco-2 and HT-29 cell lines, and HPeV-1 replication in Caco-2 cells, whereas the other compounds showed limited or variable effects. In contrast, in HIE, remdesivir and ribavirin reduced EV-A71 replication in only one donor, while itraconazole and posaconazole exhibited donor-specific cytotoxicity. No compound consistently inhibited HPeV-1 replication across HIE donors despite detectable antiviral effect in cell lines. Comparative analysis of drug-metabolising enzyme expression did not fully account for donor-specific response variability. Collectively, these findings reveal substantial heterogeneity in antiviral responses that is not captured by standard cell lines and underscore the value of incorporating genetically and physiologically diverse human organoid-based models into preclinical antiviral screening pipelines to improve translational fidelity.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106422"},"PeriodicalIF":4.0,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760575","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":"Overview of gene editing strategies against HBV","authors":"Zak T. Janetzki ,&nbsp;Laura C. McCoullough ,&nbsp;Peter A. Revill ,&nbsp;Margaret Littlejohn","doi":"10.1016/j.antiviral.2026.106355","DOIUrl":"10.1016/j.antiviral.2026.106355","url":null,"abstract":"<div><div>254 million people currently live with chronic hepatitis B virus (HBV) infection, with over 1 million deaths annually due to complications such as cirrhosis and hepatocellular carcinoma. Although current direct-acting antivirals suppress HBV replication, they do not eliminate the virus and rarely lead to HBV functional cure, defined as the loss of serum hepatitis B surface antigen (HBsAg) and DNA. A major barrier to achieving HBV functional cure is the HBV covalently closed circular DNA minichromosome (cccDNA), which hides from the immune system in the nucleus of an infected cell, and is very stable. Another barrier is integration of incomplete HBV genomes into the host genome, which is the main source of HBsAg in later disease stages, and is difficult to target without impacting the human genome. New direct-acting antivirals are required that target different stages of the HBV replication cycle, including the HBV cccDNA and integrated DNA to improve rates of functional cure. The development of gene editing tools provides an opportunity to develop novel therapies that target the HBV cccDNA, integrated DNA and HBV RNA. This review explores the different gene editing tools that have been used to target the HBV cccDNA, integrated DNA and RNA.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106355"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028384","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 UL23 thymidine kinase of Marek's disease virus is a target for anti-HSV drug development","authors":"Yunzhe Kang ,&nbsp;Rui Wang ,&nbsp;Lulu Yao ,&nbsp;Xiuwen Yang ,&nbsp;Wenhui Zhu ,&nbsp;Lele Wang ,&nbsp;Gaiping Zhang ,&nbsp;Guoqing Zhuang ,&nbsp;Aijun Sun","doi":"10.1016/j.antiviral.2026.106344","DOIUrl":"10.1016/j.antiviral.2026.106344","url":null,"abstract":"<div><div>Marek's disease virus (MDV) is an oncogenic alphaherpesvirus causing rapid onset of malignant T-cell lymphomas in chickens. <em>UL23</em>-encoded thymidine kinase (TK) has highly conserved sequences in distinctive alphaherpesviruses. However, its enzymatic activity in viral replication and pathogenesis is poorly understood. Here, we found that the nucleotide-binding sites and the functional domains related to activity of TK from different alphaherpesviruses are strongly conserved. We show that an MDV-1 <em>UL23</em>-null mutation (Md5BACΔ<em>UL23</em>) significantly reduces MDV replication <em>in vitro</em> and <em>in vivo</em>. Interestingly, chimeric viruses with replacement of MDV-1 <em>UL23</em> with MDV-2, HVT, PRV, or HSV-1 <em>UL23</em> showed partial recovery of MDV replication and pathogenicity. In addition, Md5BACΔ<em>UL23</em> infection resulted in higher survival rate and lower MDV-specific tumor incidence, which could be partially compensated by chimeric viruses. The replication properties of <em>UL23</em> chimeric alphaherpesviruses are susceptible to acyclovir inhibition, whereas Md5BACΔ<em>UL23</em> exhibits complete resistance. Overall, our establishment of the MDV-TK chimeric model provides a robust basis for evaluating TK-targeted therapeutics, accelerating clinical translation of novel anti-herpesvirus strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106344"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987929","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":"Targeted organic acid profiling in Crimean-Congo hemorrhagic fever: A metabolomics-based approach to biomarker discovery","authors":"Halef Okan Doğan ,&nbsp;Seyit Ali Büyüktuna ,&nbsp;Gözde Ertürk Zararsız ,&nbsp;Serra İlayda Yerlitaş ,&nbsp;Ahu Cephe ,&nbsp;Ahmet Turan Koç ,&nbsp;Rıdvan Karaarslan ,&nbsp;Zülal Peri Yoldaş Aslanoğlu ,&nbsp;Merve Gülşah Lafçı ,&nbsp;Meltem Kurt Yenihan ,&nbsp;Alperen Aydemir ,&nbsp;Ebrar Büşra Yıldırım ,&nbsp;Gökmen Zararsız","doi":"10.1016/j.antiviral.2026.106358","DOIUrl":"10.1016/j.antiviral.2026.106358","url":null,"abstract":"<div><div>Crimean-Congo Hemorrhagic Fever (CCHF) is a severe tick-borne viral infection associated with high morbidity and mortality. Understanding the metabolic alterations associated with the disease may uncover novel biomarkers for diagnosis and disease severity assessment. In this study, we conducted a targeted metabolomic analysis using LC-MS/MS to quantify serum organic acid levels in 115 CCHF-positive patients, 30 CCHF-negative patients, and 45 healthy controls. This is the first study to comprehensively profile organic acid alterations in CCHFV using targeted metabolomics. Our findings revealed that several organic acids, notably alpha-ketoglutaric acid, malic acid, p-hydroxyphenyllactic acid, and 3-hydroxyisobutyric acid, were significantly elevated in CCHFV patients and positively correlated with markers of inflammation and coagulation. These metabolites demonstrated strong prognostic performance for intensive care unit (ICU) admission. Additionally, survival analysis indicated that elevated levels of specific organic acids were associated with increased mortality risk. Pathway enrichment analysis identified dysregulation of the TCA cycle, pyruvate metabolism, and amino acid pathways in CCHF patients. Our results suggest that specific organic acids may serve as novel biomarkers for disease severity and prognosis, offering potential tools for early risk stratification and improved clinical management of CCHF.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106358"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic intranasal delivery of NanoSTING provides broad protection against seasonal and highly pathogenic influenza strains","authors":"Ankita Leekha ,&nbsp;Kate Reichel ,&nbsp;Brett Hurst ,&nbsp;Navin Varadarajan","doi":"10.1016/j.antiviral.2026.106342","DOIUrl":"10.1016/j.antiviral.2026.106342","url":null,"abstract":"<div><div>Influenza is a major global threat due to several factors, including great zoonotic potential, ongoing antigenic drift, limited effectiveness of current vaccines, and the emergence of drug-resistant viral strains. Broad-spectrum therapeutic regimens that can treat vulnerable populations, enable faster resolution of symptoms, and decrease fatality rates are a long-sought objective for influenza. Here, we report the development of NanoSTING, a liposomally encapsulated STING agonist (cGAMP), as a single-dose intranasal treatment of influenza. We demonstrate that NanoSTING is stable under simple refrigeration conditions, with no loss of encapsulated cGAMP, for up to a year. A single dose of NanoSTING administered intranasally induced robust type I interferon responses in the nasal and lung tissue of mice without observable toxicity. In mouse challenge models of influenza A (H1N1 or highly pathogenic H5N1) and influenza B, NanoSTING provided therapeutic protection at least as effective as ten doses of oseltamivir. NanoSTING demonstrated therapeutic efficacy even when administered 48–72 h post-infection. Furthermore, NanoSTING maintained its activity in aged and immunocompromised mice, as evidenced by the robust induction of interferon responses in nasal tissues, highlighting its potential for use in vulnerable individuals. These attributes of NanoSTING support its potential use as a promising host-directed anti-viral with a large therapeutic window and broad-spectrum efficacy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106342"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987548","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":"Lapachol, a dihydroorotate dehydrogenase inhibitor, demonstrates antiviral activity against feline calicivirus in vitro and in vivo","authors":"Zexin Liu ,&nbsp;Guohong Wu ,&nbsp;Jianwei Mao ,&nbsp;Yutong Zheng ,&nbsp;Qizhen Fu ,&nbsp;Sifan Lin ,&nbsp;Yizhou Chen ,&nbsp;Weisan Chen ,&nbsp;Pei Zhou ,&nbsp;Jianxin Chen","doi":"10.1016/j.antiviral.2026.106354","DOIUrl":"10.1016/j.antiviral.2026.106354","url":null,"abstract":"<div><div>Feline calicivirus (FCV) infection poses a significant threat to domestic cats, causing a spectrum of clinical symptoms ranging from mild respiratory issues to severe systemic diseases. Although FCV vaccines are available, their protective efficacy is limited by the extensive genetic diversity and antigenic variability of FCV. To date, no approved antiviral drug is available, highlighting the urgent need for effective therapeutics. Here, we screened a library of 431 small-molecule compounds to identify novel antiviral agents against FCV, leading to the discovery of ten new inhibitors, including five naphthoquinones. Among these, lapachol demonstrated the most potent anti-FCV activity, with a half-maximal effective concentration (EC₅₀) of 1.87 μM and a selectivity index (SI) of 677. Mechanistic studies revealed that lapachol exerts its antiviral effects by inhibiting feline dihydroorotate dehydrogenase (DHODH), thereby disrupting the synthesis of pyrimidine nucleotides, which are essential for viral replication. Further investigations showed that silencing DHODH enhanced lapachol's antiviral activity, while supplementation with pyrimidine nucleotides or DHODH overexpression reversed its effects. Importantly, oral administration of lapachol at 5 mg/kg significantly reduced virus shedding from the oral and nasal cavities in FCV-infected cats, promoted recovery from weight loss, and alleviated oral ulceration and pulmonary lesions, without inducing observable hepatic or renal toxicity. These findings demonstrate that lapachol is a promising candidate for the treatment of FCV infections, and underscore the potential of DHODH as a viable therapeutic target for antiviral drug development.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106354"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040284","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":"Pharmacokinetics and safety of HIV fusion inhibitor Lipovirtide in non-human primates","authors":"Yuanmei Zhu ,&nbsp;Huihui Chong ,&nbsp;Nian Liu,&nbsp;Yuxian He","doi":"10.1016/j.antiviral.2026.106357","DOIUrl":"10.1016/j.antiviral.2026.106357","url":null,"abstract":"<div><div>Lipovirtide, also known as LP-80, is a lipopeptide-based HIV fusion inhibitor with potent broad-spectrum and long-lasting antiviral activity. We recently reported the pharmacokinetics and safety of Lipovirtide in rats (Zhu et al. 2025); herein, its pharmacokinetics and safety profiles in cynomolgus macaques were systematically evaluated. Lipovirtide was rapidly absorbed after subcutaneous administration, with absolute bioavailability (F) of 110.11 % in male and 92.33 % in female. The time to reach maximum plasma concentration (T_max) ranged from 4 to 8 h, and the terminal half-life (T_1/2) was between 10.18 and 13.51 h. Comprehensive safety assessments revealed no significant effects on cardiovascular or respiratory functions in conscious macaques after a single subcutaneous administration. General toxicity studies demonstrated its excellent tolerability, with a maximum tolerated dose above 150 mg/kg for single dosing; the 4-week and 39-week repeated dosing determined the no-observed-adverse-effect level (NOAEL) to be 15 mg/kg. Toxicokinetic analyses confirmed that long-term administration did not lead to drug accumulation in both male and female animals. No anti-drug antibody (ADA) formation was observed throughout the study schedule. Collectively, our preclinical characterizations provide compelling data to support the clinical development of Lipovirtide, which has already progressed to a phase III clinical trial.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106357"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050165","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 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}