An international team of researchers has achieved a significant milestone by determining the first high-resolution structures of the herpes simplex virus origin-binding protein (OBP). This breakthrough, which has been published in Nucleic Acids Research, reveals critical insights into the mechanisms of HSV-1 DNA replication and identifies multiple potential targets for new antiviral drugs.
The research, conducted by scientists from the Karolinska Institutet, the University of Gothenburg, and the Centre for Structural Systems Biology in Hamburg, utilized cryo-electron microscopy (cryo-EM) to capture detailed images of OBP at resolutions up to 2.8 Å. These structures illustrate the protein’s interactions with viral DNA origin sequences and its complex formation with an ATP analogue, shedding light on the initial stages of the herpes virus replication process.
Martin Hällberg, the corresponding author from the Department of Cell and Molecular Biology at Karolinska Institutet, emphasized the importance of this discovery. “Current HSV-1 treatments almost exclusively target the viral DNA polymerase, and we’re seeing increasing resistance to these drugs, especially in immunocompromised patients,” he noted. “OBP represents an entirely new target that acts even earlier in the viral lifecycle, before the polymerase is recruited.”
Key Findings and Implications
The research uncovered several unexpected features of OBP. Contrary to previous assumptions, the protein forms a head-to-tail dimer, exhibiting a unique regulatory mechanism. The extreme C-terminus of each protein threads through its partner, positioning closely to the ATP-binding pocket. This finding resolves a long-standing paradox where deletion of this region enhanced helicase activity but reduced overall replication efficiency.
Emil Gustavsson, the first author of the study, explained, “The C-terminus appears to act as an intrinsic brake on helicase activity. 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.”
The high-resolution images identified several promising sites for antiviral drug development. The unique DNA-binding motif essential for the virus to recognize replication origins is a potential target, as is the dimer interface crucial for protein stability and functionality. Furthermore, the ICP8-binding region that influences helicase activity could serve as another avenue for intervention. Notably, the ATP-binding pocket’s unusual configuration may allow the creation of highly specific inhibitors.
“We’ve essentially provided a molecular blueprint for drug design,” said Per Elias, a co-author from the University of Gothenburg. “These diverse targeting options could help overcome resistance mechanisms and potentially even prevent viral reactivation from latency.”
The Urgency of New Treatments
With approximately 70% of the global population carrying HSV-1, the need for alternative treatments is pressing. Symptoms can range from cold sores to severe conditions like encephalitis. The emergence of drug-resistant strains, particularly in immunocompromised individuals, has heightened the urgency for new antiviral therapies.
This issue is especially critical for cancer patients undergoing chemotherapy or bone marrow transplantation, as these treatments can suppress the immune system, triggering reactivation of latent herpesviruses. When resistance to current medications arises, clinicians often resort to less effective or more toxic alternatives, such as foscarnet, underscoring the necessity for innovative therapeutic options.
There is also growing interest in the potential role of neurotropic herpesviruses, like herpes simplex and varicella zoster virus, in neurodegenerative diseases. Developing new drugs aimed at preventing viral reactivation from latency could provide valuable alternatives for preventing and treating these serious conditions.
The research received support from the Swedish Research Council, the Swedish Cancer Foundation, and the Helmholtz Association. The cryo-EM data were collected at the 3D-EM facility at Karolinska Institutet and the Centre for Structural Systems Biology in Hamburg. The findings are accessible to the broader scientific community, with structural coordinates, cryo-EM maps, and raw data deposited in the Protein Data Bank, Electron Microscopy Data Bank, and the Electron Microscopy Public Image Archive.
