New class of antivirals targets host cell structure to block HSV-1
A promising development from recent research suggests that a class of antivirals known as Pin1 inhibitors could prevent or significantly reduce outbreaks of herpes simplex virus 1 (HSV-1), the virus behind oral herpes and cold sores. The study, published in Antiviral Research, highlights a novel way to curb the virus by manipulating a host cell enzyme rather than directly attacking the virus itself.
HSV-1 infects a large portion of the global population, with estimates showing that between 50% and 90% of people carry the virus. After the initial infection, HSV-1 remains dormant in the body and can reactivate, causing recurrent sores around the mouth. While most infections are mild, they can pose serious risks for immunocompromised individuals. This has created urgency for more effective antiviral strategies.
How Pin1 inhibitors work against HSV-1
The key focus of the research is the enzyme peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, commonly known as Pin1. This enzyme regulates protein stability, function, and cellular structure. In many conditions, Pin1 becomes dysregulated, and viruses are known to interact with Pin1 as part of their life cycle.
Researchers investigated whether Pin1 inhibitors could stymie HSV-1 by targeting this host factor. Lead investigator Professor Takemasa Sakaguchi from Hiroshima University explains that Pin1 is a crucial therapeutic target for HSV-1 proliferation. In laboratory tests, the Pin1 inhibitors significantly suppressed HSV-1 replication at low concentrations.
Laboratory findings and the mechanism at work
In experiments using VeroE6 cells, a standard cell line in virology, HSV-1-infected cultures were treated with several Pin1 inhibitors, including a compound known as H-77. As inhibitor concentrations increased, the virus’s impact on the cells diminished, and viral replication stopped at 1 μM. Importantly, any virus particles released from treated cells were non-infectious, suggesting a robust shutdown of viral spread.
The standout discovery concerns how Pin1 inhibitors alter cellular architecture to trap the virus inside the nucleus. Normally, the viral nucleocapsids must breach the nuclear membrane to exit the cell and infect others. HSV-1 overexpression of Pin1 can undermine this barrier. But H-77 and related inhibitors strengthen the nuclear lamina, creating a thicker, more impregnable barrier that physically prevents viral escape.
Sakaguchi described the effect as turning the nuclear lamina into a defensive wall. “The nuclear lamina initially functions as a barrier when nucleocapsids of progeny viruses bud from the nuclear membrane. Pin1 overexpressed by the virus removes this barrier. However, through the action of the Pin1 inhibitor H-77, this barrier is reinforced, forming a thick and robust lamina layer. This demonstrates that H-77 transforms the nuclear lamina into an ‘impregnable defensive wall’,” he said.
What this could mean for the future of HSV-1 treatment
Although the results come from early laboratory studies, they open a promising path toward host-directed therapeutics—treatments that target human cellular factors rather than the virus itself. Such an approach may reduce the likelihood of drug resistance developing, a common challenge with traditional antivirals.
Looking ahead, researchers plan to assess Pin1 inhibitors across a broader range of viruses and work on optimizing the compound structures to improve potency and selectivity. The team envisions clinical applications once efficacy and safety are established in further studies.
“The ultimate goal for the future is to aim for the clinical application of Pin1 inhibitors as ‘host-directed therapeutics,’ which are less likely to cause drug resistance,” said Sakaguchi. “To achieve this, we will first evaluate their efficacy against diverse viruses to clarify the treatable range.”
Potential impact beyond HSV-1
If Pin1 inhibitors prove effective against HSV-1, the research may also spark exploration into treatments for other viral infections that exploit Pin1 during replication. This could lead to a new class of antivirals that protect not just oral herpes but a broader spectrum of viral diseases.
