Scientists Reveal First High-Resolution Structure of Key Herpes Virus Protein, Opening Path to New Antivirals

Using cryo-electron microscopy (cryo-EM), researchers from Karolinska Institutet, the University of Gothenburg, and the Centre for Structural Systems Biology in Hamburg captured detailed snapshots of OBP at resolutions up to 2.8 Å. The structures show the protein in multiple functional states—bound to viral DNA origin sequences and complexed with an ATP analogue—providing unprecedented insights into the earliest stages of herpes virus replication.

"This is particularly important because current HSV-1 treatments almost exclusively target the viral DNA polymerase, and we're seeing increasing resistance to these drugs, especially in immunocompromised patients," said corresponding author Martin Hällberg from The Department of Cell and Molecular Biology at Karolinska Institutet. "OBP represents an entirely new target that acts even earlier in the viral lifecycle, before the polymerase is recruited."

Unexpected Architecture Reveals Regulatory Mechanisms

The structures revealed several surprises. Rather than the previously proposed arrangement, OBP forms a head-to-tail dimer with a unique regulatory mechanism: the extreme C-terminus of each protein molecule threads through its partner, positioning itself near the ATP-binding pocket. This explains a long-standing paradox—why deletion of this region enhances helicase activity but reduces overall replication efficiency.

"The C-terminus appears to act as an intrinsic brake on helicase activity," explained first author Emil Gustavsson from CSSB Centre for Structural Systems Biology. "When the viral single-stranded DNA-binding protein ICP8 binds to OBP, it likely releases this brake, coordinating the transition from origin recognition to active DNA unwinding."

Multiple Drug Targets Identified

The high-resolution structures identify several potential sites for antiviral drug development. The unique DNA-binding motif that recognizes viral origins represents one promising target, as it is essential for the virus to identify where to begin replication. The dimer interface, which is required for protein stability and function, offers another avenue for intervention. 

Additionally, the ICP8-binding region that regulates helicase activity could be targeted to disrupt the coordination between viral proteins. Perhaps most intriguingly, the structures reveal an unusual configuration of the ATP-binding pocket that differs from other helicases, potentially allowing for the development of highly specific inhibitors.

"We've essentially provided a molecular blueprint for drug design," said co-author Per Elias from the University of Gothenburg. "These diverse targeting options could help overcome resistance mechanisms and potentially even prevent viral reactivation from latency, and, perhaps as important, we will now be able to precisely address regulatory features of viral DNA replication during latency and lytic replication”.

Implications Beyond Current Therapies and Implications for Cancer Patients

With approximately 70% of the global population carrying HSV-1, and symptoms ranging from cold sores to potentially fatal encephalitis, the need for alternative treatments is urgent. The emergence of drug-resistant strains, particularly in immunocompromised patients, has made the development of new antivirals a priority.