Enteroviruses, a large family of pathogens, are responsible for viral infections in humans ranging from mild colds to more severe illnesses like meningitis, paralysis, and heart inflammation. Despite their significant impact on public health, the development of effective vaccines and antiviral treatments has been hampered by the viruses’ remarkable ability to mutate and their complex interactions with cells.
The development of vaccines and antivirals is hindered by the extraordinary ability of enteroviruses to mutate.
Now, an international study led by the Institute of Integrative Systems Biology (I2SysBio) of the Spanish National Research Council (CSIC) and the National Institute of Allergy and Infectious Diseases (NIAID) in the United States has identified shared vulnerabilities within these viruses. The research offers a potential pathway toward broad-spectrum antiviral therapies.
The study, published in Nature Ecology & Evolution, reveals a stable core region in two enteroviruses – Enterovirus A71 and Coxsackievirus B3 – and a region with minimal variation in the protein 2C, which is crucial for the replication of many of these pathogens responsible for millions of infections each year. These findings position these regions as promising targets for the development of broad-spectrum antiviral drugs.
Preventing Drug Resistance
Researchers mapped more than 80,000 mutations to analyze how they affect the function of two clinically relevant human enteroviruses: Enterovirus A71 (EVA71), which can cause neurological conditions such as encephalitis and meningitis, and Coxsackievirus B3 (CVB3), which can lead to pancreatitis or myocarditis.
“This mapping was performed using an ultra-rapid genetic screening method known as deep mutational scanning, which allows us to simultaneously evaluate the effect of tens of thousands of different mutations,” explained Beatriz Álvarez, a researcher at I2SysBio and an author of the article.
The results allowed researchers to identify regions of the virus that are universal, essential, and invariable, as well as those that vary depending on the type of virus.
The results identified regions of the virus that are universal, essential, and invariable, and those that vary depending on the virus type – whether it’s EVA71, which affects the brain, or CVB3, which is linked to heart complications – and its adaptive strategy to evade the host’s immune system. This understanding is critical for designing modern antivirals that target these stable areas, blocking the virus’s ability to escape through mutations and preventing the development of drug resistance.
“Discovering the regions that change throughout viral evolution helps us understand how new functions arise in viruses and how interactions with hosts develop over time,” Álvarez added.
Vulnerable Regions of the Viruses
The research reveals that both EVA71 and CVB3 share a stable ‘core’ that includes the fundamental components necessary for viral replication and assembly of the capsid – the protein shell that encloses and protects the virus’s genetic material. These parts are highly resistant to change and represent ideal weak points.
“If these areas are targeted with an antiviral, it is very difficult for the virus to escape through mutations without losing its ability to infect,” detailed Ron Geller, a principal author of the study and leader of the Viral Biology group at I2SysBio.
Conversely, the areas that vary the most between the two viruses studied are those they apply to interact with cells, such as regions on the exterior of the capsid that bind to different cellular receptors. These differences explain why each enterovirus infects different tissues or causes illnesses of varying severity.
New Research Opportunities
Identifying regions that change throughout the evolutionary history of viruses also provides insight into how new viral functions emerge and how interactions between viruses and hosts evolve over time.
Identifying regions that change throughout the history of viral evolution allows us to understand how new viral functions arise.
“These findings open up new research opportunities: on one hand, identifying a potential therapeutic target allows us to apply in silico virtual screening approaches (computer simulations) to discover compounds capable of blocking these viruses, which is particularly relevant given the current lack of effective antivirals,” Geller stated.
“it offers the possibility of studying how very similar viruses can evolve to use different cellular factors during their replication, providing valuable information about both viral and host biology,” he concluded.
New Pocket in Protein 2C
Another key finding of the study is the identification of a new structural pocket in protein 2C, a region critical for viral replication. This is a cavity on its surface designed to interact with other molecules, facilitating the development of drugs that can fit into that space to alter the protein’s structure and, abolish its biological function.
“This highly conserved region is very promising as an antiviral target, as it is present and conserved not only in the two viruses analyzed, but also in other viruses of the same family,” Álvarez detailed. Because this area allows for very few changes, an antiviral directed toward that region would have a high potential to function against many enteroviruses at once, while also having a low probability of generating resistance.
Reference:
Beatriz Álvarez-Rodríguez, et al. ‘Comparative Analysis of Deep Mutational Scanning Datasets in Enteroviruses A and B Identifies Functional Divergence and Therapeutic Targets’. Nature Ecology & Evolution 2026.
Rights: Creative Commons.
