A team led by structural biologists at the University of Maryland, Baltimore County has produced the most detailed picture yet of how enteroviruses, the viral family behind polio, viral myocarditis, and the common cold, physically break into human cells and hijack them. Their findings, published in Nature Communications in early 2025, reveal that a short, folded stretch of RNA shared across these viruses acts as a master switch for replication, while the virus’s outer shell executes a precisely choreographed shape change that ends with a custom-built pore punched through the cell membrane.
The discovery matters because the mechanism is nearly identical in poliovirus, coxsackievirus, and rhinovirus. If a single molecular trick underlies all three infections, a single drug might be able to block it.
A viral break-in, step by step
Enteroviruses are small, rugged, and spectacularly successful. The genus contains more than 300 known serotypes and causes an estimated billions of respiratory infections each year, along with rarer but devastating outcomes: paralysis from poliovirus, inflammation of the heart muscle from coxsackievirus B strains, and acute flaccid myelitis linked to enterovirus D68. Despite decades of research and the triumph of polio vaccines, no broad-spectrum antiviral drug exists for the group. Pleconaril, a capsid-binding compound that reached late-stage clinical trials in the early 2000s, was never approved by the FDA for the common cold due to modest efficacy and drug-interaction concerns.
The new work attacks the problem from the inside out. Using high-resolution structural methods, the UMBC team resolved how a piece of RNA called the 5-prime cloverleaf, sitting at the very front of the viral genome, physically grabs two viral proteins known as 3C and 3CD. That handshake is the trigger for negative-strand RNA synthesis, the first copying step the virus must complete after entering a cell. The Nature Communications paper presents atomic-level structures of this RNA-protein complex and shows the interaction is conserved across multiple enterovirus species, making it a single potential drug target relevant to several diseases.
“We were struck by how little variation there is in this part of the machinery across viruses that cause very different diseases,” said the study’s senior investigators at UMBC, describing the cloverleaf-protein interface as unexpectedly rigid given the diversity of the enterovirus genus.
But replication cannot begin until the genome gets inside the cell. That is where the capsid’s transformation comes in.
The capsid shape-shift
When an enterovirus latches onto its receptor on a human cell, its protein shell does something remarkable. The compact particle, known as the 160S form, swells into a larger, looser structure called the 135S intermediate. Cryo-electron microscopy reconstructions of this poliovirus intermediate, first described in detail in 2013 and still the benchmark structure for the field, show a capsid primed for membrane contact and genome release.
During that expansion, two internal peptides, VP4 and the amino-terminal extension of VP1, swing outward through channels in the shell and embed themselves in the host cell’s lipid membrane. What follows is not a crude rupture. Experiments using reconstituted lipid membranes have shown that rhinovirus VP4, once externalized, assembles into a multimeric pore large enough to thread RNA through but selective enough to exclude bigger molecules. The virus, in effect, builds a controlled tunnel rather than blasting a hole.
Cryo-EM comparisons of RNA-filled rhinovirus particles and their empty shells add another layer: structural apertures appear only after the genome exits, and capsid-RNA interactions visible in the full particle help explain how the genome stays organized during assembly and detaches cleanly during uncoating. Separate structural work has captured two distinct conformational states in a single particle, reinforcing the idea that cell entry is a programmed sequence of shape changes, not a one-step collapse.
What the research has not yet shown
The structural picture is compelling, but several gaps remain between laboratory reconstructions and what happens in a living human airway or heart muscle cell.
The VP4 pore data come entirely from reconstituted liposome systems. No electrophysiology recordings of VP4 pore currents in intact human cells have been published, leaving open questions about conductance, ion selectivity under physiological conditions, and whether host-cell proteins might crowd or stabilize the channel. Whether VP4 pores behave the same way in a cardiac myocyte as they do in a synthetic lipid bubble is unknown.
The 2013 poliovirus 135S reconstruction, while detailed, has not been superseded by a substantially higher-resolution structure. Some fine details, such as the exact path VP1’s amino-terminal extension takes as it threads through the capsid into the membrane, are inferred rather than resolved at side-chain level.
Most importantly for anyone hoping this leads to a pill, the Nature Communications paper does not report drug candidates, binding affinities for inhibitors, or animal efficacy data. No small-molecule screen results or lead compound structures have been disclosed. The leap from “shared structure” to “shared drug target” is scientifically grounded but unproven. It is also unclear whether targeting the cloverleaf interaction alone would exert enough antiviral pressure to avoid viral escape mutations, or whether combination approaches would be needed.
The structural work covers poliovirus and selected rhinovirus and coxsackievirus strains, but the enterovirus genus also includes EV-D68, which has been linked to waves of acute flaccid myelitis in children, and EV-A71, a cause of severe hand, foot, and mouth disease in Asia. Sequence conservation of the cloverleaf motif suggests the mechanism applies broadly, but direct structural confirmation is missing for many clinically important serotypes.
From structural map to antiviral blueprint
What the UMBC team and converging lines of research from other groups have produced, as of June 2026, is a near-atomic map of a shared vulnerability. A conserved RNA element at the front of the genome orchestrates the start of replication by recruiting viral enzymes. Simultaneously, the capsid undergoes a series of expansions and peptide externalizations that culminate in a VP4-lined pore through which the RNA exits into the host cell. The strength of this picture lies in the convergence of multiple structural methods and biochemical assays across several virus types.
For the public, the practical meaning is this: scientists now understand, in fine-grained detail, a shared lock-and-key arrangement that enteroviruses use both inside and outside their protein shells. That understanding does not guarantee a broad-spectrum antiviral will emerge, but it provides a rational blueprint for designing one, something the field has lacked.
Future work will need to show that small molecules or biologics can disrupt the cloverleaf-protein interaction or the VP4 pore in living cells and animal models, and that such disruption meaningfully reduces disease. Drug development from a validated target to an approved therapy typically takes a decade or more. But for a virus family that still paralyzes children, inflames hearts, and sends millions to bed with colds every year, having a detailed structural map of the break-in is a significant step past guesswork.
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*This article was researched with the help of AI, with human editors creating the final content.
