Ann E. Tollefson , Anna Cline-Smith , Vincent Roy , Luigi A. Agrofoglio , Getahun Abate , Franck Gallardo , Karoly Toth
{"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":null,"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":4.5000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antiviral research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0166354225001470","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.