Antiviral research最新文献

{"title":"Update on combination therapies against HBV in clinical investigations","authors":"Lung-Yi Mak ,&nbsp;Anna SF. Lok","doi":"10.1016/j.antiviral.2025.106321","DOIUrl":"10.1016/j.antiviral.2025.106321","url":null,"abstract":"<div><div>Functional cure has been proposed to be the treatment endpoint of cure therapies in chronic hepatitis B (CHB), yet it is rarely achieved with monotherapy of novel virus-targeting agents or immunomodulators. Although translation inhibitors – small interfering RNAs (siRNAs) and antisense oligonucleotides can produce marked decline in hepatitis B surface antigen (HBsAg) levels, the response is often not sustained and HBsAg seroclearance rarely occur after treatment cessation, suggesting that pharmacological reduction in HBsAg level may be insufficient in restoring HBV-specific immune response. Increasing number of studies have adopted the combination approach with virus-directing agent(s) plus immunomodulator(s). To date, the most effective regimen involves the concurrent or sequential use of siRNA with PEG-IFNα for 48 weeks, with resultant off-therapy HBsAg seroclearance rates approaching 30 %, and functional cure rates of up to 10 %. Other immunomodulators studied in combination with siRNA such as toll-like receptor agonists, therapeutic vaccines, monoclonal hepatitis B surface antibodies, and immune checkpoint inhibitors are less effective. Almost all studies included NUC and only a few evaluated protocolized NUC withdrawal; thus, few studies have truly evaluated functional cure. Low baseline HBsAg level is the most reliable predictor of HBsAg seroclearance, with many trials exclusively enrolling patients with HBsAg level &lt;200 to &lt;1000 IU/mL. While recent studies have shown promise, further research is needed to determine the optimal classes of drugs to combine, duration of use for each drug and whether they should be used concurrently or sequentially, to meet the desired goal of 30 % functional cure rate.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"245 ","pages":"Article 106321"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of HBV replication and expression by CRISPR/Cas9 ribonucleoproteins","authors":"Addison C. Hill ,&nbsp;Madison B. Schank ,&nbsp;Yi Zhang ,&nbsp;Ning Sun ,&nbsp;Ling Wang ,&nbsp;Juan Zhao ,&nbsp;Puja Banik ,&nbsp;Jaeden S. Pyburn ,&nbsp;Holly Orfield ,&nbsp;Janet W. Lightner ,&nbsp;Tabitha O. Leshaodo ,&nbsp;Xiao Y. Wu ,&nbsp;Shunbin Ning ,&nbsp;Mohamed El Gazzar ,&nbsp;Jonathan P. Moorman ,&nbsp;Haitao Guo ,&nbsp;Zhi Q. Yao","doi":"10.1016/j.antiviral.2025.106326","DOIUrl":"10.1016/j.antiviral.2025.106326","url":null,"abstract":"<div><div>HBV infection is a global public health problem. The current treatment using nucleotide analogues (NA) can suppress viral replication but cannot eliminate HBV infection due to the persistence of covalently closed circular DNA (cccDNA), which sustains HBV replication and integration into the host cell genome and is refractory to NA treatment. CRISPR/Cas9 has been used to disrupt integrated HBV DNA and minichromosomal cccDNA for HBV suppression, but its expression and delivery require viral or non-viral vectors, which pose safety concerns for human application. We have previously reported the use of synthetic guide RNA (gRNA)/Cas9 ribonucleoprotein (RNP) as a non-viral formulation for HBV gene editing and viral suppression. To formulate highly effective CRISPR/Cas9 modalities for HBV gene therapy, here we designed additional gRNA/Cas9 RNPs and compared their antiviral efficacy in HBV-transfected as well as -infected cells. We found that two selected gRNA/Cas9 RNPs (gRNA5/Cas9, gRNA9/Cas9, and particularly their combinations) elicited the most potent antiviral efficacy, as evidenced by the significant inhibition of HBV DNA, RNA, and protein productions. DNA sequencing of the treated cells revealed moderate to high rates of insertion and deletion (indel) or knock-out (KO) mutations at the HBV target genes. Gene alignment analysis showed a high level of conservation for both gRNA5 and gRNA9 target sequences across major HBV genotypes, indicating that these CRISPR-based gene editing therapeutics have the potential to target different HBV strains worldwide. Thus, these synthetic gRNA/Cas9 RNPs represent promising novel therapeutics that can be developed and utilized for HBV gene disruption and viral eradication.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"245 ","pages":"Article 106326"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733830","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 inhibition of IGF2BP1 effectively suppresses HBV replication via an m6A-dependent manner","authors":"Deyao Li ,&nbsp;Yuxin Song ,&nbsp;Danjuan Lu ,&nbsp;Yanhua Zhang ,&nbsp;Chenxiao Qu ,&nbsp;Guiwen Guan ,&nbsp;Yuexi Ma ,&nbsp;Tianhao Mao ,&nbsp;Liwei Zheng ,&nbsp;Yi Wang ,&nbsp;Wenhui Song ,&nbsp;Ting Zhang ,&nbsp;Fengmin Lu ,&nbsp;Jing Ning ,&nbsp;Xiangmei Chen","doi":"10.1016/j.antiviral.2025.106310","DOIUrl":"10.1016/j.antiviral.2025.106310","url":null,"abstract":"<div><div>Elucidation of the regulation mechanism of hepatitis B virus (HBV) replication will provide potential targets for the development of novel anti-HBV therapeutics. It has been reported that the N6-methyladenosine (m6A) modification of HBV RNA plays a crucial role in the HBV life cycle. However, the mechanisms underlying the regulation of this modification remain incompletely understood. In this study, combining loss- and gain-of-function genetic analyses, we defined the role of IGF2BP1, an m6A reader, in facilitating HBV replication. Mechanistic studies revealed that IGF2BP1 stabilizes HBV RNAs primarily by binding to m6A-modified A1907 sites through its KH3-4 domain, thereby enhancing viral replication. Furthermore, targeted inhibition of IGF2BP1 by Cucurbitacin B, a small molecule inhibitor of IGF2BP1, was shown to inhibit HBV replication <em>in vitro</em> and <em>in vivo</em>. Taken together, these findings identify IGF2BP1 as a critical host regulator of HBV RNA stability through an m6A-dependent manner and targeted inhibition of IGF2BP1 effectively attenuates viral replication, providing a promising strategy for anti-HBV drug development.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"245 ","pages":"Article 106310"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581632","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":"Bulevirtide for chronic hepatitis delta: from clinical trials to real life data: an expert opinion report","authors":"Tarik Asselah ,&nbsp;Homie Razavi ,&nbsp;Hélène Fontaine ,&nbsp;Kosh Agarwal","doi":"10.1016/j.antiviral.2025.106311","DOIUrl":"10.1016/j.antiviral.2025.106311","url":null,"abstract":"<div><div>Hepatitis D virus (HDV) is a small RNA virus that requires Hepatitis B Surface Antigen (HBsAg) for its envelope. Eight genotypes with more than 80 % sequence homology and many subgenotypes have been described. Worldwide prevalence of chronic hepatitis delta (CHD) is estimated at about 5 % of chronic hepatitis B cases, translating to 15–20 million individuals. The diagnosis of HDV infection involves presence of antibodies to hepatitis D antigen (anti-HDV antibodies). <em>Anti-HDV total antibody indicates HDV exposure (not infection). To document infection; the patient needs to undergo PCR testing and only if PCR is positive should the diagnosis of HDV ongoing infection done.</em> Testing for the antibodies should be performed in all HBsAg-positive persons. CHD is more severe and progressive than HBV mono-infection, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC), <em>transplantation and death</em>. Pegylated interferon-alpha (pegIFN-a) has been used for treating CHD with only limited durable responses. A 48-week course of weekly subcutaneous injections of pegIFN-a suppresses HDV replication in approximately 20–30 % of patients 24 weeks off therapy, with significant side effects. Bulevirtide (BLV) was approved by the European Medicines Agency (EMA) in 2020 for CHD and compensated liver disease. Since its approval, real-life data on the use of BLV have been accumulating, with most treated patients in Europe having advanced fibrosis or cirrhosis. Real life data efficacy is concordant to that seen in clinical trials, with many patients achieving significant reductions in HDV RNA levels and ALT normalization after several months of treatment, and favorable safety. However, HBsAg loss is relatively rare. Finite therapy of BLV, in combination with pegIFN-a, leads to significant durable response, with more than 30 % of patients achieving HDV RNA undetectability off therapy. We need new finite therapies. Further real-world data and newer therapies are required for this severe disease.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"245 ","pages":"Article 106311"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572894","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":"Novel computational pipeline to identify target sites for broad spectrum antiviral drugs","authors":"John D. Sears ,&nbsp;Konstantin I. Popov ,&nbsp;Paul A. Sylvester ,&nbsp;Rebekah Dickmander ,&nbsp;Jennifer Diaz ,&nbsp;Che-Kang Chang ,&nbsp;Julia Huff ,&nbsp;Wes Sanders ,&nbsp;Nicholas A. Saba ,&nbsp;Madeleine Sorensen ,&nbsp;Adam M. Drobish ,&nbsp;Nicholas A. May ,&nbsp;Kevin Namitz ,&nbsp;Julia Fecko ,&nbsp;Neela H. Yennawar ,&nbsp;Thomas E. Morrison ,&nbsp;Alexander Tropsha ,&nbsp;Mark T. Heise ,&nbsp;Nathaniel J. Moorman","doi":"10.1016/j.antiviral.2025.106322","DOIUrl":"10.1016/j.antiviral.2025.106322","url":null,"abstract":"<div><div>Emerging viruses pose an ongoing threat to human health. While certain viral families are common sources of outbreaks, predicting the specific virus within a family that will cause the next outbreak or pandemic is not possible, creating an urgent need for broad spectrum antiviral drugs that are effective against a wide array of related viral pathogens. However, broad spectrum drug development is hindered by the lack of detailed knowledge of compound binding sites that are structurally and functionally conserved between viral family members and are essential for virus replication. To overcome this limitation, we developed an in silico approach that combines AI-driven protein structure prediction, computational fragment soaking, multiple sequence alignment, and protein stability calculations to identify highly conserved target sites that are both solvent-accessible and conserved. We applied this approach to the <em>Togaviridae</em> family, which includes emerging pandemic disease threats such as chikungunya and Venezuelan equine encephalitis virus for which there are currently no approved antiviral therapies. Our analysis identified multiple solvent accessible and structurally conserved pockets in the alphavirus non-structural protein 2 (nsP2) protease domain, which is essential for processing the viral replicase proteins. Mutagenesis of key solvent accessible and conserved residues identified novel pockets that are essential for the replication of multiple alphaviruses, validating these pockets as potential antiviral target sites for nsP2 inhibitors. These findings highlight the potential of artificial intelligence-informed modeling for revealing functionally conserved, accessible pockets as a means of identifying potential target binding sites for broadly active direct acting antivirals.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"245 ","pages":"Article 106322"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666763","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 HBV RNA destabilizing drugs: Drugs of the future or compounds from the past?","authors":"Timothy M. Block,&nbsp;Dimitar Gotchev,&nbsp;Yanming Du","doi":"10.1016/j.antiviral.2025.106288","DOIUrl":"10.1016/j.antiviral.2025.106288","url":null,"abstract":"<div><div>Small-molecule HBV RNA destabilizing agents, such as the dihydroquinolizinones (DHQs), were first disclosed in a patent filing in 2015 and in peer reviewed literature in 2018. These compounds inhibit Poly-adenylating Polymerases 5 and 7 (PAPD5/7) and represent a novel antiviral strategy and their ability to degrade hepatitis B surface antigen (HBsAg) in cell culture and animal models generated considerable excitement and commercial interest. However, extrahepatic toxicity observed in preclinical and Phase I studies led to the discontinuation of several development programs. The subsequent emergence of liver-targeted PAPD5/7 inhibitors with improved safety profiles has rekindled interest in this therapeutic approach. Yet, with the apparent success of other investigational antivirals in reducing HBsAg levels, such as siRNAs, antisense oligonucleotides, and in at least one example, capsid assembly modulators (CAMs), questions remain as to whether RNA destabilizers still have a role in managing chronic hepatitis B (CHB). This review describes the current status of PAPD5/7 inhibitor development, evaluates the advantages and limitations of the approach, and considers potential strategies for integrating this class of molecules with other HBV therapies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106288"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257217","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":"Ciclopirox suppresses poxvirus replication by targeting iron metabolism","authors":"Anil Pant ,&nbsp;Djamal Brahim Belhaouari ,&nbsp;Lara Dsouza ,&nbsp;D.M. Nirosh Udayanga ,&nbsp;Zhengqiang Wang ,&nbsp;Zhilong Yang","doi":"10.1016/j.antiviral.2025.106290","DOIUrl":"10.1016/j.antiviral.2025.106290","url":null,"abstract":"<div><div>Poxviruses remain a significant global health concern, necessitating the development of novel antiviral strategies. Through high-throughput screening, we previously identified ciclopirox (CPX), an FDA-approved antifungal, as a hit that inhibits vaccinia virus (VACV) replication. Here, we further characterized its antiviral activity and mechanism of action using human primary fibroblasts. CPX significantly reduced VACV titers without reducing host cell viability, with an EC₅₀ in the sub-micromolar range and a CC₅₀ &gt; 500 μM. Rescue experiments demonstrated that CPX inhibits viral replication primarily through chelation of intracellular Fe³⁺ and, to a lesser extent, Fe²⁺, as evidenced by partial restoration of viral replication with ferric ammonium citrate supplementation. Furthermore, overexpression of the iron-dependent enzymes RRM2 and the VACV-encoded F4L reduced the inhibitory effect of CPX, indicating that these host and viral proteins are affected by CPX treatment. Moreover, CPX treatment suppressed cowpox virus and monkeypox (mpox) virus replication <em>in vitro</em>. It also reduced VACV titers in <em>ex vivo</em> mouse lung tissue. These findings highlight host iron metabolism as a critical determinant of poxvirus replication and identify CPX as a promising antiviral candidate against multiple orthopoxviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106290"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257245","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 natural polyphenol proanthocyanidin A2 prevents the in vitro infection of Ebola virus and rabies virus by interfering with the early phases of the replication cycle","authors":"Denis Pasqual ,&nbsp;Ilaria Artusi ,&nbsp;Michele Paccagnella ,&nbsp;Giulia Sibille ,&nbsp;Mattia Mirandola ,&nbsp;Sofia Appelberg ,&nbsp;Maria Francesca Priore ,&nbsp;Maira Zorzan ,&nbsp;Massimo E. Maffei ,&nbsp;Paola De Benedictis ,&nbsp;Claudia Del Vecchio ,&nbsp;Alì Mirazimi ,&nbsp;Giorgio Cozza ,&nbsp;Giorgio Gribaudo ,&nbsp;Cristiano Salata","doi":"10.1016/j.antiviral.2025.106312","DOIUrl":"10.1016/j.antiviral.2025.106312","url":null,"abstract":"<div><div>The Ebola virus (EBOV) and the Rabies virus (RABV) are deadly infectious agents impacting human and animal health. Current prevention and control strategies mainly rely on vaccines and antibodies, highlighting the urgent need for effective, low-cost antivirals suitable for therapeutic options. Plant-derived bioactive compounds offer a promising natural source for such candidate antivirals. As a contribution to this antiviral approach, we have characterized the anti-EBOV and anti-RABV activity of a Cranberry extract (CE) endowed with a very high content of bioactive A2-type proanthocyanidin (PAC-A2). The CE inhibited the <em>in vitro</em> infection of both pseudoviruses expressing EBOV-GP or RABV-G glycoproteins and authentic EBOV and RABV. Attachment and entry assays revealed that the extract targets early phases of infection preventing attachment and entry. Noteworthy, synthetic PAC-A2 reproduced the antiviral activity observed with the whole CE. Mechanistic studies then revealed that the CE interacted directly with the ectodomain of EBOV-GP or the RABV-G, suggesting interference with their functions. In support to this hypothesis, fluorescence spectroscopy analysis showed a reduction in intrinsic fluorescence of both EBOV-GP and RABV-G after incubation with synthetic PAC-A2, thus confirming a direct interaction of the viral glycoproteins with PAC-A2. <em>In silico</em> docking simulations further sustained <em>in vitro</em> results by predicting the binding of PAC-A2 into the binding pocket of EBOV-GP and to the trimeric architecture of RABV-G.</div><div>Together, these results suggest this cranberry extract and bioactive PAC-A2 as potential candidates to be further develop as novel antiviral agents for the prevention of EBOV and RABV infections.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106312"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576257","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":"Genetic determinants of efficacy of antiviral drugs revealed by genome-wide CRISPR screens","authors":"Wei Jiang ,&nbsp;Ailing Yang ,&nbsp;Jingchuan Ma ,&nbsp;Dawei Lv ,&nbsp;Mingxian Liu ,&nbsp;Chao Wang ,&nbsp;Shuo Chen ,&nbsp;Huiling Fang ,&nbsp;Yankai Chu ,&nbsp;Zhengjin He ,&nbsp;Wenrui Li ,&nbsp;Yucheng Liu ,&nbsp;Yun Zhao ,&nbsp;Zhaocai Zhou ,&nbsp;Gang Long ,&nbsp;Hai Jiang","doi":"10.1016/j.antiviral.2025.106309","DOIUrl":"10.1016/j.antiviral.2025.106309","url":null,"abstract":"<div><div>Nucleoside and nucleobase analog antiviral drugs are pivotal in antiviral therapy, but comprehensive methods to understand their cellular response mechanisms and genetic regulators are still lacking. Here, we show that Eμ-Myc; Arf^−/− mouse lymphoma cells, which are highly apoptosis-prone, enabled genome-wide CRISPR-Cas9 screening on such drugs to identify genes that modulate their efficacy. Using retroviral sgRNA libraries and MAGeCK analysis, we uncovered key regulators of drug transport, activation, and inactivation for these drugs. For ribavirin, adenosine kinase (ADK) and adenylsuccinate synthase (ADSS) were critical for nucleotide metabolism and bioactivation. Remdesivir uptake and activation depended on the transporter SLC29A3 and phosphoamidase HINT1, whereas favipiravir resistance was linked to NT5C2-mediated dephosphorylation. Viral replication assays in Huh7 cells validated that knockout of SLC29A3, HINT1, or NT5C2 significantly altered antiviral efficacy. This study delineates the genetic network governing nucleotide analog response, providing mechanistic insights and potential biomarkers for personalized antiviral therapy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106309"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556140","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":"Pivotal animal efficacy studies supporting brincidofovir licensure under the FDA animal rule","authors":"Daniel C. Sanford ,&nbsp;Melicia R. Gainey ,&nbsp;Cheryl Triplett ,&nbsp;Irma M. Grossi ,&nbsp;Scott A. Foster ,&nbsp;Jeffry D. Shearer ,&nbsp;Shantha Kodihalli","doi":"10.1016/j.antiviral.2025.106302","DOIUrl":"10.1016/j.antiviral.2025.106302","url":null,"abstract":"<div><div>Brincidofovir (BCV, commercially known as Tembexa®) is an antiviral drug with broad-spectrum activity against orthopoxviruses. BCV was approved under the FDA Animal Rule for the treatment of human smallpox disease in adult and pediatric patients, including neonates. Rabbitpox (RPXV) and mousepox (ectromelia, ECTV) models were used to evaluate the survival benefit of oral BCV treatment. Progression of clinical disease, including clinical signs of disease, body weight change, body temperature, respiration rate (rabbits only) and viral load, was also compared in BCV-treated and placebo treated animals. In rabbits, oral BCV treatment was administered as 20, 5 and 5 mg/kg doses 48 h apart beginning on RPXV post-inoculation day (PID) 3, 4, 5, or 6. In mice, oral BCV treatment was administered as 10, 5 and 5 mg/kg doses 48 h apart beginning on ECTV PID 4, 5, or 6 or as 20, 5 and 5 mg/kg doses 48 h apart beginning on ECTV PID 4, 5, 6, or 7. BCV prevented death caused by RPXV or ECTV infection when treatment was initiated at the latest PID time point evaluated in each model. BCV treatment did not markedly affect clinical observations compared to placebo in either model. Viral load was reduced at the two earliest PID treatment points in rabbits. Viral load was not evaluated statistically in mice, however terminal liver viral loads tended to be higher with either dose regimen when BCV treatment was delayed. These studies formed the basis for approval of BCV by the FDA Animal Rule.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"244 ","pages":"Article 106302"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413770","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}