New Pin1 Inhibitors Offer a New Way to Combat Cold Sores
Researchers are exploring a novel class of antivirals that could change how we prevent and treat oral herpes. Pin1 inhibitors, designed to target a cellular enzyme called peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), have shown potential to curb herpes simplex virus 1 (HSV-1) replication. HSV-1 is the virus behind most cold sores, a common infection worldwide that can reactivate throughout a person’s life. While the condition is usually mild, it can be severe for people with weakened immune systems, underscoring the need for better treatments.
What Pin1 Does and Why It Matters for HSV-1
Pin1 regulates protein stability, function, and cellular structure. When Pin1 is dysregulated, it can contribute to a range of health issues, from metabolic disorders to cancer. Viruses, including HSV-1, often manipulate Pin1 to promote their own replication. In this recent study, researchers noted that HSV-1–infected cells overexpress Pin1, making the enzyme a compelling target for antiviral strategies that act on the host cell rather than the virus itself.
“The host factor Pin1 is a crucial therapeutic target for the proliferation of HSV-1. Pin1 inhibitors potently suppress HSV-1 replication at low concentrations,” explained Takemasa Sakaguchi of Hiroshima University. This host-focused approach aims to reduce the likelihood of drug resistance, a common challenge with treatments that directly attack viral components.
Key Laboratory Findings
The team tested the Pin1 inhibitor H-77 alongside four newly developed Pin1 inhibitors in cell culture models. Using VeroE6 cells, a standard lab line derived from African green monkey kidneys, researchers infected the cells with HSV-1 and exposed them to varying doses of the inhibitors. As inhibitor levels rose, HSV-1’s impact on the cells diminished, and complete suppression occurred at about 1 micromolar concentration. Moreover, any viral particles released from treated cells were non-infectious, suggesting a robust block to viral spread.
Crucially, the study demonstrated a unique mechanism: inhibiting Pin1 helped preserve and strengthen the nuclear lamina—the membrane surrounding the cell’s nucleus. Normally, after replication, viral capsids must exit the nucleus to form new virus particles. HSV-1 can disrupt the nuclear barrier to escape, a process that Pin1 overexpression facilitates. By contrast, Pin1 inhibitors reinforce this barrier, effectively trapping viral components inside the nucleus and preventing the release of infectious virions.
Implications for Cold Sore Treatment
The findings point to a promising direction for treating HSV-1 using host-directed therapeutics. By targeting a host enzyme rather than a viral protein, these drugs could be less prone to resistance—a major advantage for long-term herpes management. The researchers emphasize that Pin1 inhibitors could potentially be developed into therapies that reduce or prevent outbreaks, improving quality of life for millions affected by cold sores.
Beyond HSV-1, Pin1 is involved in various cellular processes implicated in other viruses. The researchers plan to assess the inhibitors against a broader range of pathogens and to refine the compounds for potency and selectivity. The overarching goal is a clinically applicable class of Pin1 inhibitors capable of boosting cellular defenses against multiple viral infections.
What Comes Next
Future work will focus on validating the efficacy of Pin1 inhibitors across diverse viral models and optimizing their chemical structures to maximize antiviral activity while minimizing side effects. As Sakaguchi notes, the long-term aim is to translate these findings into safe, effective therapies that function as host-directed antivirals, offering durable protection with a lower risk of resistance.
