Enteroviruses represent a diverse group of RNA viruses responsible for a wide array of diseases ranging from mild respiratory illnesses to severe neurological complications. Despite their global prevalence and impact on millions annually, effective broad-spectrum treatments have remained elusive. Recent groundbreaking research from the Norwegian University of Science and Technology (NTNU) has identified a synergistic combination of orally available drugs that show potent activity against enteroviruses in human cells and organoid cultures, marking a promising leap forward in antiviral therapy.
Enteroviruses, members of the Picornaviridae family, encompass over 100 distinct types including polioviruses, coxsackieviruses, and echoviruses. These pathogens are notorious for their ability to cause diseases such as aseptic meningitis, myocarditis, hand, foot and mouth disease, and even chronic conditions potentially linked to type 1 diabetes. The viruses replicate intracellularly using host cellular machinery, rapidly generating progeny viruses that disseminate infection throughout the body. The lack of a universal antiviral or vaccine against this heterogeneous group has been a significant hurdle for clinicians and researchers alike.
An important reason for the absence of an approved general treatment regimen might lie in the fact that many enterovirus infections are self-limiting. The host immune system often clears the virus naturally, leading to a reduced perceived urgency in developing specific therapeutics. However, severe cases leading to neurological damage, paralysis, or fatal outcomes highlight a critical unmet medical need. Children and immunocompromised individuals remain particularly vulnerable, thus necessitating a treatment approach capable of broadly targeting various enterovirus strains.
The new study conducted by NTNU researchers focuses on inhibiting viral replication, a strategy that targets the fundamental process by which enteroviruses propagate. Viral replication is heavily reliant on viral proteases and polymerases, enzymes critical for processing viral polyproteins and synthesizing viral RNA genomes respectively. By obstructing these enzymes’ activity, the virus can be prevented from reproducing, stopping the infection at its foundation.
Utilizing a library of known antivirals, the research team screened combinations of agents to discover synergistic effects that could enhance antiviral potency while minimizing toxicity. They identified a promising cocktail comprising pleconaril, AG7404, and mindeudesivir — all previously tested for safety in humans. Pleconaril acts primarily by binding to a viral capsid, preventing viral uncoating and entry into host cells. AG7404 is an inhibitor targeting the viral 3C protease, essential for cleavage of viral polypeptides. Mindeudesivir, a nucleoside analog, inhibits viral RNA-dependent RNA polymerase activity, thereby blocking genome replication.
In vitro experiments demonstrated that this three-drug combination effectively halts enterovirus replication in human cell lines and organoid cultures derived from intestinal and cardiac tissues. Organoids, miniature 3D cultures that simulate human organs, offer a sophisticated platform for evaluating the efficacy and safety of therapeutics under physiologically relevant conditions. Importantly, the combination’s antiviral effect did not perturb critical cellular functions such as glucose metabolism or insulin secretion in pancreatic tissue models — a key consideration given the established links between enterovirus infections and type 1 diabetes pathogenesis.
Moreover, cardiovascular safety was assessed using heart organoids, where the drug combination did not induce arrhythmias or alter heart rates. These data are particularly reassuring because many antiviral candidates may exhibit off-target cardiotoxic effects, limiting their clinical viability. The oral bioavailability of the drugs offers additional advantages, simplifying administration and potentially increasing patient compliance compared to injectable antivirals.
The research extends earlier findings where combinations including pleconaril, rupintrivir, and remdesivir demonstrated broad-spectrum activity but suffered practical limitations. Rupintrivir and remdesivir require separate dosing due to formulation constraints, complicating treatment regimens. The substitution of rupintrivir and remdesivir with AG7404 and mindeudesivir respectively retains efficacy while creating a more practical single-pill therapy. This innovation underscores the importance of not only antiviral potency but also pharmaceutical development considerations such as dosing convenience.
Extensive testing encompassed 12 antiviral agents, both individually and in various combinations, against diverse enterovirus strains in lung epithelial cells and intestinal organoids. Such rigorous screening helps identify agents capable of targeting conserved viral functions, thereby increasing the likelihood of broad-spectrum efficacy across enterovirus species. These investigations provide valuable insight into the biochemical interactions and potential resistance liabilities inherent to combination therapy.
The implications of this study are far-reaching. A safe, effective, and easily administrable antiviral cocktail could transform the clinical management of enterovirus infections, particularly in pediatric populations and immunocompromised patients at risk of severe disease. Furthermore, the ability to inhibit multiple enteroviruses supports preparedness against future outbreaks and emerging strains with unpredictable pathogenic potential.
Despite these encouraging findings, the researchers emphasize the necessity for further studies to validate efficacy and safety in vivo and ultimately in human clinical trials. Comprehensive evaluation across multiple enterovirus types will be critical, as genetic diversity may influence drug susceptibility. Additionally, long-term impact studies on organ systems and immune responses will ensure that therapeutic benefits outweigh any adverse effects.
The innovative approach of repurposing safe-in-man molecules combined with intricate organoid modeling sets a new benchmark for antiviral drug development. It opens pathways toward tackling other challenging viral families where effective treatments remain absent. This study exemplifies how collaboration among molecular biology, pharmacology, and clinical medicine can accelerate translating basic research into tangible health solutions.
In summary, the NTNU team’s discovery of a synergistic drug trio inhibiting enterovirus replication in human cells and organoids represents a major stride in the antiviral field. With further refinement and clinical validation, this combination holds promise as the first broad-spectrum oral antiviral against enteroviruses, addressing a longstanding clinical void and potentially improving outcomes for millions worldwide affected by these pervasive pathogens.
Subject of Research: Cells
Article Title: Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures.
News Publication Date: 23-Jan-2025
Web References: http://dx.doi.org/10.1007/s00018-025-05581-4
References: Ravlo, E., Ianevski, A., Schjølberg, JO. et al. Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures. Cell. Mol. Life Sci. 82, 57 (2025).
Image Credits: Photo: Idun Haugan, NTNU
Keywords: Enterovirus, antiviral therapy, pleconaril, AG7404, mindeudesivir, organoid culture, viral replication inhibitors, broad-spectrum antivirals, RNA viruses, drug synergy, oral antiviral, NTNU
Tags: broad-spectrum antiviral therapychronic conditions linked to enterovirusesenterovirus family viral infectionsenterovirus-related diseasesenteroviruses antiviral treatmentsimmune response to enterovirusesNorwegian University of Science and Technology researchnovel antiviral drug discoveryoral drug combination effectivenesspoliovirus coxsackievirus echovirusRNA viruses disease preventionviral replication mechanisms
