A Newly Discovered Virus Weak Spot Could Change Future Treatments

Key Points:

• Researchers at the University of Maryland, Baltimore County have mapped, at atomic resolution, how enteroviruses initiate replication inside human cells by revealing the interaction between a cloverleaf-shaped viral RNA structure and the viral fusion protein 3CD.
• The cloverleaf RNA acts as a molecular switch, recruiting 3CD to initiate negative-strand RNA synthesis, shifting the virus from protein production to replication; two copies of the 3C protein bind the RNA's sD stem-loop subdomain, a key interaction resolved via X-ray crystallography.
• The sD stem-loop structure is highly conserved across seven enteroviral species, including poliovirus and rhinoviruses, with protein binding depending on RNA backbone recognition, suggesting a universal structural target for antiviral drug development.
• The study identifies a new potential drug target at the RNA-protein interface, as disrupting the cloverleaf-3C interaction could inhibit viral replication; the conserved nature of this structure makes it less prone to mutation and viral resistance.
• Findings also clarify that the 3CD precursor binds the cloverleaf with higher affinity than 3C alone, aided by a flexible linker region, highlighting the sophisticated mechanisms enteroviruses use despite their minimal genomes.