UMBC team maps enterovirus 'on-off switch' for replication
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- Deepak Koirala's lab at UMBC, with Ph.D. graduate Naba Krishna Das, published in Nature Communications the first high-resolution structure of enterovirus RNA bound to the replication protein 3CD, resolving how the virus hijacks human cells to copy itself.
- The team showed that the 3C domain of the 3CD fusion protein binds a cloverleaf-shaped structure in the viral RNA and then recruits the host protein PCBP2 to assemble the full replication complex — with 3C cutting proteins and 3D acting as the RNA polymerase human cells lack.
- 3CD functions as a molecular switch: when attached to the RNA cloverleaf, the virus copies its genome; when detached, the RNA is free to produce viral proteins — a dual-control mechanism the team visualized directly.
- Using X-ray crystallography, isothermal titration calorimetry, and biolayer interferometry, the researchers settled a longstanding debate by showing that two full 3CD molecules (each carrying its own polymerase) bind side by side on the RNA, not as a single fused pair as earlier work had proposed.
- The cloverleaf structure and 3CD binding behavior were nearly identical across all seven enteroviruses examined, suggesting the site is so essential that mutations would likely kill the virus — and giving drug developers a conserved, mutation-resistant target across an entire virus family.
- Koirala says the findings open a third drug-design lane: beyond 3C and 3D protein inhibitors already in development, compounds could be designed to break the RNA-protein interface itself, a strategy made possible by the new high-resolution structures.
Why it matters: Targeting the conserved cloverleaf RNA-protein interface could let a single drug work against the entire enterovirus family — polio, myocarditis, encephalitis, common cold — rather than requiring separate pathogen-specific antivirals. Because the structure was identical across all seven viruses tested, mutations there would likely be lethal, giving any new drug a durable, resistance-resistant target. With 3C/3D inhibitors already in development, this adds a parallel drug-design strategy rather than replacing existing pipelines.
