New antiviral strategy targets host cell structures to combat HSV-1
Researchers are exploring a novel class of antivirals that go beyond directly attacking viruses. Pin1 inhibitors, a group of compounds that modulate the host enzyme peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), have shown promise in curbing herpes simplex virus 1 (HSV-1) replication. HSV-1 is the virus behind oral herpes, commonly known as cold sores or fever blisters. While most people encounter HSV-1 during childhood and carry the virus for life, outbreaks can recur, causing discomfort and, in rare cases for individuals with weakened immune systems, serious health risks. The new study, published in Antiviral Research, positions Pin1 inhibitors as a potential host-directed therapeutic approach with the aim of reducing outbreaks and transmission.
Why Pin1 matters in HSV-1 infection
Pin1 is an enzyme that regulates protein stability, function, and cellular structure. In several viral infections, HSV-1 included, infected cells show overexpression of Pin1. This excess Pin1 appears to support viral replication, making it a compelling target for intervention. “The host factor Pin1 is a crucial therapeutic target for the proliferation of HSV-1,” noted Takemasa Sakaguchi of Hiroshima University. By inhibiting Pin1, researchers hypothesized that they could disrupt the virus’s ability to hijack cellular environments to replicate.
Laboratory findings: inhibition reduces HSV-1 replication
In controlled lab experiments, the Pin1 inhibitor H-77, along with four newly developed Pin1 inhibitors, successfully halted HSV-1 replication. Researchers used VeroE6 cells, derived from the kidney of an African green monkey and widely used in virology, which were infected with HSV-1 and treated with varying concentrations of Pin1 inhibitors. As inhibitor levels rose, the virus’s deleterious effects on the cells diminished, with complete suppression observed at 1 μM. Importantly, viral particles released from treated cells were non-infectious, signaling that the inhibitors can neutralize viral spread at the source.
How Pin1 inhibitors disrupt the virus life cycle
The standout finding centers on how Pin1 inhibitors affect cell structure to trap the virus inside the cell. HSV-1 nucleocapsids mature in the nucleus and must escape through the nuclear membrane to assemble new viral particles. Normally, Pin1 overexpression helps the virus dismantle this barrier, easing viral egress. However, Pin1 inhibitors reverse this process: they stabilize the nuclear lamina, making it thicker and more robust. This fortified nuclear barrier acts like an impregnable defensive wall, physically preventing the virus from exiting the nucleus and spreading to other cells.
“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,” explained Sakaguchi. The result is a cellular environment that hinders HSV-1 replication and release, offering a unique method to suppress infection without relying solely on direct-acting antivirals.
What this means for future treatments
While these findings are early and based on cellular models, they open avenues for host-directed antiviral therapies. Targeting Pin1 could reduce the likelihood of drug resistance that often arises with traditional antivirals focused on viral components. The research team emphasizes that the ultimate goal is clinical application of Pin1 inhibitors as host-directed therapeutics, which may guard against a broad range of viruses and enhance treatment options for HSV-1 and beyond.
Next steps in research
Researchers plan to evaluate Pin1 inhibitors across diverse viruses to map the full treatment range and optimize compound structures for greater potency and selectivity. Additional studies will assess safety, delivery methods, and efficacy in more complex biological systems. If these efforts prove successful, Pin1 inhibitors could become part of a new class of antivirals designed to fortify host cellular defenses rather than solely attacking invading pathogens.
