Cell-Penetrating Receptor Mimic Delivers a Long-Sought Blow Against Enteroviruses

Hand, foot, and mouth disease is usually dismissed as a routine childhood illness, yet its most severe forms are caused by two closely related viruses that continue to claim young lives across Asia and beyond. Enterovirus A71, often abbreviated EV-A71, and its frequent companion coxsackievirus A16 are the leading viral culprits behind serious cases of the disease, capable of progressing from fever and blistering rashes to life-threatening brainstem encephalitis, pulmonary edema, and death in infants and small children. Despite decades of research and the deployment of vaccines in some countries, no specific antiviral drug against these pathogens has reached clinical practice, leaving physicians to manage the sickest patients with supportive care alone.

A team led by Shijin Wang, Yubin Tang, and colleagues, writing in PLOS Pathogens, now reports a molecule that may change that picture. The researchers describe RMP(R8), an engineered peptide that mimics the part of a human protein called SCARB2, which the viruses use as their essential gateway into cells. In laboratory tests the compound blocked EV-A71 and CV-A16 at remarkably low concentrations, showed an excellent safety profile, and improved survival in a lethal neonatal mouse model of infection. The work also resolves a paradox that has frustrated antiviral developers for roughly a decade, and in doing so proposes a new playbook for drugging virus-receptor interactions that occur deep inside cells rather than on their surfaces.

To appreciate why the finding matters, it helps to understand how these viruses gain entry. EV-A71 and CV-A16 belong to the genus Enterovirus within the family Picornaviridae, small non-enveloped viruses whose outer shell is built from four structural proteins arranged with icosahedral symmetry. For enteroviruses of this group, attachment to a surface receptor is only the first act. The truly decisive step, known as uncoating, occurs after the virus has been taken up into the cell, when the protein shell rearranges or releases its RNA genome so replication can begin. SCARB2, a lysosomal membrane protein found abundantly on many human cell types, is the receptor that triggers this uncoating reaction. Structural studies have shown that binding of the virion to SCARB2 destabilizes the capsid, converting the virus into an expanded particle that expels its genome into the cytosol.

That mechanism suggests an obvious therapeutic strategy, at least on paper. If a soluble fragment of SCARB2 floating outside the cell could latch onto incoming virus particles and prematurely trip their uncoating switch, the virus would fall apart harmlessly in extracellular fluid. Such receptor decoys have succeeded against other pathogens, and researchers duly built Fc-fusion proteins carrying the extracellular domain of SCARB2. The results were consistently disappointing. The decoys failed to neutralize EV-A71 in meaningful ways, a puzzle that has stood in the literature for some ten years and discouraged further investment in SCARB2-based antivirals. The reason, as the new study makes clear, is that SCARB2 does its critical work not on the cell surface but inside the endosomal and lysosomal compartments, where the acidity and protease environment differ dramatically from conditions outside the cell and where a large, bulky Fc-fusion protein simply cannot follow the virus.

The team’s solution was to shrink the receptor to its functional core and smuggle it to where it is needed. Mining the structure of the SCARB2-virion interface, they identified a short stretch of the protein, spanning amino acids W146 through K166, as the minimal region that binds VP2, one of the capsid proteins on the viral shell. They fused this twenty-one-residue binding domain to octa-arginine, a classical cell-penetrating peptide composed of eight positively charged arginine residues. The result is RMP(R8), an intracellular receptor mimetic: small enough to cross cell membranes and enter the cytosol and vesicular compartments, yet retaining the binding surface that the virus itself recognizes. In effect, the molecule impersonates the receptor inside the cell, contacting virus particles at the very stage where extracellular decoys are absent and where premature engagement spells disaster for the pathogen.

The numbers reported for the compound are striking. RMP(R8) inhibited EV-A71 with a half-maximal effective concentration of 0.156 micrograms per milliliter, a potent value for a peptide antiviral. Its selectivity index, the ratio comparing the dose that harms host cells with the dose that blocks the virus, exceeded 2003, indicating a wide therapeutic margin. The peptide also dissolved readily in water, an unglamorous but decisive property for any molecule hoping to be formulated, dosed, and distributed clinically. In cultured cells derived from the intestine and the nervous system, tissues that matter most for enterovirus disease, RMP(R8) suppressed infection by genetically divergent EV-A71 isolates as well as by CV-A16, suggesting the activity is not confined to a single laboratory strain but extends across the viral diversity that vaccines and strain-specific antibodies struggle to cover.

Mechanistically, the authors traced the compound’s action to the blockage of viral entry. Rather than preventing attachment to the cell surface, RMP(R8) interferes with the intracellular step at which SCARB2 normally catalyzes uncoating. By engaging the virion’s VP2-binding site at the wrong time and place, the mimetic presumably triggers or locks the capsid into a state that cannot deliver its genome productively. This timing explains the failure of the older decoys and the success of the new one: the virus is vulnerable to receptor mimicry only after it has entered the cell, and only a molecule that reaches that compartment can exploit the vulnerability. The concept is generalizable in principle. Any virus that performs its key receptor-dependent step intracellularly, and there are several among the picornaviruses and related families, could in theory be targeted by a cell-penetrating mimetic of the relevant receptor domain.

Animal testing provided the strongest evidence that the approach survives contact with a living system. In a lethal neonatal mouse model, the standard challenge assay for EV-A71 pathogenesis, treatment with RMP(R8) significantly increased survival of infected pups following challenge with EV-A71 and with CV-A16 alike. Neonatal mice lack a mature immune system and are exquisitely susceptible to these viruses, so a survival benefit in this setting is a meaningful benchmark for a candidate antiviral. The breadth across two distinct viral species is particularly notable, because cross-species coverage is rare among antivirals that target viral enzymes or capsid pockets, which are easily undermined by a handful of point mutations. Targeting the conserved receptor-binding surface, by contrast, raises the genetic barrier to escape.

Considerable work remains between a promising peptide and an approved medicine. RMP(R8) must still demonstrate an acceptable pharmacokinetic profile, stability against proteases, appropriate tissue distribution, and safety in larger animals, and the dosing window in human infection, where treatment would likely begin after symptom onset, will need careful definition. Cell-penetrating peptides also face well-known questions about delivery and clearance in patients. Even so, the study stands out for solving a concrete mechanistic puzzle: it explains why extracellular SCARB2 decoys failed, and it converts that explanation into a working drug candidate with potency, breadth, and in vivo efficacy. For the millions of children at risk of severe hand, foot, and mouth disease each year, and for the clinicians who currently have nothing specific to offer them, an intracellular receptor mimetic that attacks EV-A71 and CV-A16 at their most vulnerable moment represents exactly the kind of targeted therapy the field has been waiting for. It also redraws the boundary of antiviral design, showing that the inside of the cell, long considered hostile territory for receptor-based drugs, can be reached and exploited.

Subject of Research: Intracellular SCARB2 receptor mimicry as a broad antiviral strategy against enteroviruses causing hand, foot, and mouth disease

Article Title: Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses

Article References: Wang, S., Tang, Y., Lai, S., Yang, J., Yang, Q., Liu, X., Yu, X.-F., Guo, H., & Wei, W. (2026). Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses. PLOS Pathogens, 22(10), e1014699. https://doi.org/10.1371/journal.ppat.1014699

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014699

Keywords: EV-A71, coxsackievirus A16, enterovirus, SCARB2, hand foot and mouth disease, antiviral peptide, receptor mimicry, viral uncoating, cell-penetrating peptide, PLOS Pathogens, neonatal mouse model, viral entry