Antiviral research最新文献

{"title":"Defining diabetic mouse as a highly susceptible preclinical model for monkeypox virus infection","authors":"Chao Shang , Minghua Chen , Yan Liu , Xiao Li , Yiquan Li","doi":"10.1016/j.antiviral.2025.106112","DOIUrl":"10.1016/j.antiviral.2025.106112","url":null,"abstract":"","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106112"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424778","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":"Effectiveness of nucleoside analogs against Wetland virus infection","authors":"Rui Wang ,&nbsp;Xi Wang ,&nbsp;Jianzhong Zhu ,&nbsp;Hao Li ,&nbsp;Wei Liu","doi":"10.1016/j.antiviral.2025.106114","DOIUrl":"10.1016/j.antiviral.2025.106114","url":null,"abstract":"<div><div>Wetland virus (WELV), a newly identified Orthonairovirus phylogenetically related to the Crimean–Congo hemorrhagic fever virus (CCHFV), has recently been shown to cause human infections. A portion of patients infected with WELV usually present with febrile diseases, accompanied by hemorrhagic and neurological symptoms. Currently, there are no reports demonstrating effective therapeutic drugs for the treatment of WELV. In this study, we evaluated the anti-WELV efficacy of five nucleoside analogs: four clinically approved drugs-ribavirin, remdesivir, molnupiravir, and sofosbuvir; and a clinical candidate 4′-fluorouridine. Ribavirin and 4′-fluorouridine strongly inhibited WELV replication <em>in vitro</em>. Remdesivir and molnupiravir showed limited antiviral activity against WELV in Huh7 cells but not in Vero cells, while sofosbuvir did not exhibit inhibitory effects. Utilizing a lethal immunocompetent mouse model of WELV infection, we found that oral administration of relatively low doses of ribavirin (25 mg/kg/day) or 4′-fluorouridine (2.5 mg/kg/day) significantly reduced the mortality of WELV-infected mice by decreasing viral titers in tissues and alleviating pathological damage. This treatment strategy retained significant efficacy even when initiated 2–4 days after infection. Additionally, we identified mutations G3033R and A3756V in the C-terminal region of the WELV L protein, which may be associated with viral resistance to ribavirin and 4′-fluorouridine. This study revealed varying degrees of anti-WELV efficacy among different nucleoside analogs and identified 4′-fluorouridine as a promising therapeutic candidate and ribavirin as a priority treatment option for WELV infection.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106114"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424781","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":"25R,26-hydroxycholesterol and an oxysterol synthetic analog inhibit Varicella zoster Virus replication","authors":"Andrea Civra ,&nbsp;Matteo Costantino ,&nbsp;Domiziana Porporato ,&nbsp;Rachele Francese ,&nbsp;Manuela Donalisio ,&nbsp;Giuseppe Poli ,&nbsp;Maura Marinozzi ,&nbsp;David Lembo","doi":"10.1016/j.antiviral.2025.106113","DOIUrl":"10.1016/j.antiviral.2025.106113","url":null,"abstract":"<div><div>Varicella-zoster Virus (VZV) is a relevant pathogen belonging to the <em>herpesviridiae</em> family. Primary VZV infection causes chickenpox, and results in latent infection of sensory ganglia. Later in life, VZV can reactivate causing herpes zoster (HZ), which can be associated with severe complications in immunocompromised individuals. Currently, the available antivirals used to treat VZV infection target the DNA replication stage; however, resistance to these drugs has been reported in both immunocompromised and immunocompetent patients. For this reason, the identification of new antiviral molecules against VZV infection is a priority. Recently our research group demonstrated that the endogenous oxysterol 25R,26-hydroxycholesterol (25R,26OHC, more commonly named 27-hydroxycholesterol) and an oxysterol synthetic analog named PFM067 inhibit herpes simplex virus (HSV) replication. In this study we explored the antiviral activity of 25-hydroxycholesterol (25OHC), 25R,26OHC, and PFM067 against VZV. We demonstrated that 25R,26OHC and PFM067 exert antiviral activity against VZV with an EC₅₀ in the low micromolar range and are able to significantly reduce the area of the viral plaques. Moreover, 25R,26OHC and PFM067 can inhibit the egress of viral glycoprotein gE from the cis-Golgi compartment, similarly to what demonstrated by our group for HSV-2. Additionally, we show that 25R,26OHC and PFM067 act synergistically when used in combination with acyclovir (ACV). The promising antiviral activity of 25R,26OHC and PFM067, along with their different mechanism of action compared to ACV, makes these molecules suitable candidates for further investigation of the molecular target of oxysterols.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106113"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiviral mechanisms and preclinical evaluation of amantadine analogs that continue to inhibit influenza A viruses with M2S31N-based drug resistance","authors":"Ian Tietjen ,&nbsp;Daniel C. Kwan ,&nbsp;Annett Petrich ,&nbsp;Roland Zell ,&nbsp;Ivi Theodosia Antoniadou ,&nbsp;Agni Gavriilidou ,&nbsp;Christina Tzitzoglaki ,&nbsp;Michail Rallis ,&nbsp;David Fedida ,&nbsp;Francesc X. Sureda ,&nbsp;Cato Mestdagh ,&nbsp;Lieve Naesens ,&nbsp;Salvatore Chiantia ,&nbsp;F. Brent Johnson ,&nbsp;Antonios Kolocouris","doi":"10.1016/j.antiviral.2025.106104","DOIUrl":"10.1016/j.antiviral.2025.106104","url":null,"abstract":"<div><div>To better manage seasonal and pandemic influenza infections, new drugs are needed with enhanced activity against amantadine- and rimantadine-resistant influenza A virus (IAV) strains containing the S31N variant of the viral M2 ion channel (M2^S31N). Here we tested 36 amantadine analogs against a panel of viruses containing either M2^S31N or the parental, M2 S31 wild-type variant (M2^WT). We found that several analogs, primarily those with sizeable lipophilic adducts, inhibited up to three M2^S31N-containing viruses with activities at least 5-fold lower than rimantadine, without inhibiting M2^S31N proton currents or modulating endosomal pH. While M2^WT viruses in passaging studies rapidly gained resistance to these analogs through the established M2 mutations V27A and/or A30T, resistance development was markedly slower for M2^S31N viruses and did not associate with additional M2 mutations. Instead, a subset of analogs, exemplified by 2-propyl-2-adamantanamine (<strong>38</strong>), but not 2-(1-adamantyl)piperidine (<strong>26</strong>), spiro[adamantane-2,2′-pyrrolidine] (<strong>49</strong>), or spiro[adamantane-2,2′-piperidine] (<strong>60</strong>), inhibited cellular entry of infectious IAV following pre-treatment and/or H1N1 pseudovirus entry. Conversely, an overlapping subset of the most lipophilic analogs including compounds <strong>26</strong>, <strong>49</strong>, <strong>60</strong>, and others, disrupted viral M2-M1 protein colocalization required for intracellular viral assembly and budding. Finally, a pilot toxicity study in mice demonstrated that <strong>38</strong> and <strong>49</strong> were tolerated at 30 mg/kg. Together, these results indicate that amantadine analogs act on multiple, complementary mechanisms to inhibit replication of M2^S31N viruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106104"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412985","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":"Lipid-targeting antiviral strategies: Current state and future perspectives","authors":"Ana-Belén Blázquez ,&nbsp;Patricia Mingo-Casas ,&nbsp;Ernesto Quesada ,&nbsp;Eva María Priego ,&nbsp;María-Jesús Pérez-Perez ,&nbsp;Miguel A. Martín-Acebes","doi":"10.1016/j.antiviral.2025.106103","DOIUrl":"10.1016/j.antiviral.2025.106103","url":null,"abstract":"<div><div>There is an urgent need for antiviral compounds effective against currently known and future viral threats. The development of host-targeting antivirals (HTAs) appears as an alternative strategy to fight viral infections minimizing the potential of resistant mutant development and potentially leading to the identification of broad-spectrum antiviral agents. Among the host factors explored for HTA strategy, lipids constitute an attractive target as many viruses, even genetically diverse, hijack specific lipids during their lifecycle. Multiple repurposing efforts have been performed to analyze the antiviral properties of lipid-targeting compounds. These studies include the analysis of the effects of cholesterol lowering drugs such as statins, cholesterol transport inhibitors, sphingolipid modulators, <em>de novo</em> lipogenesis inhibitors blocking fatty acid synthesis, compounds targeting glycerophospholipids or drugs interfering with lipid droplet metabolism. This review is focused on the current status of lipid-based or lipid-targeting antiviral strategies and their potential for the development of antiviral therapies, with special emphasis on those studies that have reached advanced stages of development such as efficacy studies in animal models or clinical trials. Whereas there is still a long way to go, multiple proof-of-concept studies and clinical evidence reinforce the therapeutic potential of these strategies warranting their further development into effective antiviral therapies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106103"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412991","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":"DHODH inhibitors: What will it take to get them into the clinic as antivirals?","authors":"Anna Luganini ,&nbsp;Donatella Boschi ,&nbsp;Marco L. Lolli ,&nbsp;Giorgio Gribaudo","doi":"10.1016/j.antiviral.2025.106099","DOIUrl":"10.1016/j.antiviral.2025.106099","url":null,"abstract":"<div><div>The emergence of new human viruses with epidemic or pandemic potential has reaffirmed the urgency to develop effective broad-spectrum antivirals (BSAs) as part of a strategic framework for pandemic prevention and preparedness. To this end, the host nucleotide metabolic pathway has been subject to intense investigation in the search for host-targeting agents (HTAs) with potential BSA activity. In particular, human dihydroorotate dehydrogenase (<em>h</em>DHODH), a rate-limiting enzyme in the <em>de novo</em> pyrimidine biosynthetic pathway, has been identified as a preferential target of new HTAs. Viral replication in fact relies on cellular pyrimidine replenishment, making <em>h</em>DHODH an ideal HTA target. The depletion of the host pyrimidine pool that ensues the pharmacological inhibition of <em>h</em>DHODH activity elicits effective BSA activity through three distinct mechanisms: it blocks viral DNA and RNA synthesis; it activates effector mechanisms of the host innate antiviral response; and it mitigates the virus-induced inflammatory response. However, despite the spectacular results obtained <em>in vitro</em>, the <em>h</em>DHODH inhibitors examined as mono-drug therapies in animal models of human viral infections and in clinical trials have produced disappointing levels of overall antiviral efficacy. To overcome this inherent limitation, pharmacological strategies based on multi-drug combination treatments should be considered to enable efficacy of <em>h</em>DHODH-targeted antiviral therapies.</div><div>Here, we review the state-of-the-art of antiviral applications of <em>h</em>DHODH inhibitors, discuss the challenges that have emerged from their testing in animal models and human clinical trials and consider how they might be addressed to advance the development of <em>h</em>DHODH inhibitors as BSA for the treatment of viral diseases.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106099"},"PeriodicalIF":4.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgenic mice expressing the human CDHR3 receptor: A sensitive RV-C infection model for the evaluation of vaccines and therapeutics","authors":"Zhenhong Zhou ,&nbsp;Rui Zhu ,&nbsp;Hongwei Yang ,&nbsp;Weixi Deng ,&nbsp;Zijie Zhang ,&nbsp;Yue Li ,&nbsp;Jiaxin Xu ,&nbsp;Ziyang Yan ,&nbsp;Ruoxi Wang ,&nbsp;Sijia Chang ,&nbsp;Zhichao Yin ,&nbsp;Yuanyuan Wu ,&nbsp;Dongqing Zhang ,&nbsp;Mujin Fang ,&nbsp;Che Liu ,&nbsp;Yuqiong Que ,&nbsp;Jun Zhang ,&nbsp;Ningshao Xia ,&nbsp;Yingbin Wang ,&nbsp;Longfa Xu ,&nbsp;Tong Cheng","doi":"10.1016/j.antiviral.2025.106102","DOIUrl":"10.1016/j.antiviral.2025.106102","url":null,"abstract":"<div><div>Rhinovirus C (RV-C) is the primary causative agent of severe acute respiratory illnesses (ARTIs) in infants and young children. The limited availability of animal models complicates the development of prophylactic and therapeutic strategies targeting RV-C. Previous studies have identified human cadherin-related family member 3 (hCDHR3) as the cellular receptor for RV-C, with its expression enabling previously unsusceptible cells to support both viral entry and replication. Recently, an adult hCDHR3 transgenic mouse model was developed to investigate the role of human stimulator of interferon genes (hSTING) in RV-C15 infection <em>in vivo</em>. However, adult mice do not support efficient RV-C15 infection. Here, we report a transgenic mouse line expressing hCDHR3 constitutively that is highly susceptible to early-life infections by multiple serotypes of RV-C, including RV-C15, RV-C2, and RV-C41. Neonatal transgenic mice infected with various RV-C strains via the intraperitoneal (i.p.) route exhibit similar symptoms, such as severe inflammation, limb paralysis, and death. Moreover, passive immunization with antisera or therapeutic antibodies can protect against lethal RV-C infection in these transgenic mice. Overall, this study provides a valuable animal model for the <em>in vivo</em> antiviral evaluation against RV-C.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106102"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372309","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":"Host-targeted antivirals against SARS-CoV-2 in clinical development - Prospect or disappointment?","authors":"André Schreiber,&nbsp;Stephan Ludwig","doi":"10.1016/j.antiviral.2025.106101","DOIUrl":"10.1016/j.antiviral.2025.106101","url":null,"abstract":"<div><div>The global response to the COVID-19 pandemic, caused by the novel SARS-CoV-2 virus, has seen an unprecedented increase in the development of antiviral therapies. Traditional antiviral strategies have primarily focused on direct-acting antivirals (DAAs), which specifically target viral components. In recent years, increasing attention was given to an alternative approach aiming to exploit host cellular pathways or immune responses to inhibit viral replication, which has led to development of so-called host-targeted antivirals (HTAs). The emergence of SARS-CoV-2 and COVID-19 has promoted a boost in this field. Numerous HTAs have been tested and demonstrated their potential against SARS-CoV-2 through <em>in vitro</em> and <em>in vivo</em> studies. However, in striking contrast, only a limited number have successfully progressed to advanced clinical trial phases (2–4), and even less have entered clinical practice. This review aims to explore the current landscape of HTAs targeting SARS-CoV-2 that have reached phase 2–4 clinical trials. Additionally, it will explore the challenges faced in the development of HTAs and in gaining regulatory approval and market availability.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106101"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143377301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PI4KB and Src/Abl host kinases as broad-spectrum antiviral strategy: Myth or real opportunity?","authors":"Maria Grazia Martina ,&nbsp;Daniele Rubini ,&nbsp;Marco Radi ,&nbsp;Valeria Cagno","doi":"10.1016/j.antiviral.2025.106100","DOIUrl":"10.1016/j.antiviral.2025.106100","url":null,"abstract":"<div><div>Viruses pose a continuous threat to human health. Limited treatment options exist for current viruses, and the risk of infections with newly emerging or re-emerging viruses is increasing. In a pandemic scenario, having a broad-spectrum antiviral to limit viral spread while developing specific antivirals and vaccines is crucial. Targeting host kinases represents a valuable strategy due to the higher barrier to resistance and the broad-spectrum activity it offers. While cells have redundant kinases for the same biological function, viruses rely on specific kinases for their replication cycle, enabling targeted antiviral action with limited toxicity.</div><div>This review focuses on two extensively studied kinase targets: the lipid kinase phosphatidylinositol 4-kinase IIIβ (PI4KB) and the tyrosine kinase proteins Src and Abl. Compounds active against these targets are reviewed in terms of the viruses they inhibit, their mechanisms of action and their stage of development. While PI4KB inhibitors have reached clinical trials, those targeting Src and Abl remain largely in the preclinical phase. Nevertheless, opportunities exist to improve potency and further understand the specific roles of these kinases in the life cycle of multiple viruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"235 ","pages":"Article 106100"},"PeriodicalIF":4.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal exposure to commensal bacterium Rothia mucilaginosa protects against influenza A virus infection","authors":"Ana Raquel Maia ,&nbsp;Loïc Gonzalez ,&nbsp;Badreddine Bounab ,&nbsp;Lucia Grassi ,&nbsp;Coralie Mousset ,&nbsp;Gaëlle Fromont-Hankard ,&nbsp;Adeline Cezard ,&nbsp;Pieter Hiemstra ,&nbsp;Thomas Baranek ,&nbsp;Christophe Paget ,&nbsp;Aurélie Crabbé ,&nbsp;Mustapha Si-Tahar","doi":"10.1016/j.antiviral.2025.106076","DOIUrl":"10.1016/j.antiviral.2025.106076","url":null,"abstract":"<div><div>The respiratory tract hosts a diverse microbial community whose composition varies with anatomical location and throughout life. <em>Rothia mucilaginosa</em>, a common commensal of the upper respiratory tract and oral cavity, has recently been recognized for its ability to inhibit bacteria-triggered pro-inflammatory responses. However, its role in modulating the immune response to viral infections such as influenza A virus (IAV) pneumonia, remains unknown. Here, we demonstrate that <em>R. mucilaginosa</em> enhances protection against IAV, promoting viral clearance, reducing inflammation, preserving bronchial and alveolar structures, and improving survival in a mouse model of influenza pneumonia. The enhanced viral clearance observed in <em>R. mucilaginosa</em>-treated mice is associated with the recruitment of innate immune cells to the lungs, including PD-L1-expressing neutrophils, alongside the production of the anti-inflammatory cytokine IL-10, both of which are known to play regulatory roles in the context of IAV infection. Together, these findings highlight <em>R. mucilaginosa</em>-mediated innate immune priming as a key protective mechanism in the respiratory tract against IAV infection.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"234 ","pages":"Article 106076"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}