When immunocompromised patients develop herpes infections that no longer respond to standard antivirals, physicians often run out of options. Jonathan Abraham, an infectious disease doctor at Brigham and Women’s Hospital, sees this frustration regularly in the clinic. His team’s new study explains, for the first time in molecular detail, how an emerging class of drugs physically stops the virus from copying itself.
Published December 29 in Cell, the work reveals how helicase-primase inhibitors (HPIs) disable a key herpes simplex virus enzyme. Using cryogenic electron microscopy and optical tweezers, researchers captured both near-atomic snapshots and real-time footage of the viral machinery stalling mid-replication. Several HPIs are already in U.S. clinical trials, and one has been approved in Japan, but until now the precise mechanism remained unclear.
Most FDA-approved herpes drugs target the virus’s DNA polymerase, the enzyme that copies the viral genome. Resistant strains can emerge over time. HPIs attack a different weak point: the helicase-primase, which unwinds the double-stranded DNA and lays down short RNA primers that allow copying to begin. It’s essentially a zipper and zipper tab working together to open the genome.
“As a clinician, it’s disheartening when medicine can cure a patient of cancer, but the patient requires immunosuppression that leaves them vulnerable to a virus that doesn’t respond to the best drugs we have to treat it,” Abraham explains.
Freezing a Shape-Shifter
The helicase-primase is constantly changing shape, which has made imaging it nearly impossible. By binding tightly to the enzyme, the inhibitors effectively froze it long enough to be visualized. At the Harvard Cryo-EM Center for Structural Biology, the team resolved the structure of the HSV-1 helicase-primase bound to several inhibitors at near-atomic resolution.
Static images alone couldn’t explain how the drugs actually stop replication. Abraham partnered with Joseph Loparo, a Harvard professor of biological chemistry and molecular pharmacology, to watch the process unfold. Loparo’s team used optical tweezers, a technique that uses focused laser light to hold and manipulate single molecules. By suspending viral DNA between microscopic beads, they observed individual helicase molecules unzip DNA one strand at a time. When tiny amounts of inhibitor were added, the motion slowed and then stopped.
The drug acts like a wedge in the gears. It doesn’t destroy the enzyme outright but causes the motor to stall, preventing the virus from copying its genome and spreading. Loparo notes that combining high-resolution structural pictures with real-time imaging of the viral proteins in action was a particular strength of the study.
A Bridge Between Viral Machines
The researchers also uncovered how the helicase-primase physically interacts with the viral polymerase during DNA replication. They identified a specific amino acid sequence, dubbed the FYNPYL motif, that allows the helicase-primase to dock with the polymerase. This molecular handshake appears across many herpesviruses, including those causing shingles and certain cancers.
By mapping these interaction surfaces, the team revealed new potential drug targets. Current HPIs are highly effective against herpes simplex but have limited reach. Understanding the physical and chemical properties of these binding sites gives researchers a roadmap for designing molecules that could treat a broader range of DNA viruses.
For physicians treating patients with drug-resistant infections, the work offers something increasingly rare: a clear mechanistic explanation paired with actionable targets for next-generation therapies.
Cell: 10.1016/j.cell.2025.11.041
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