Complex blocking HPV in skin cancer without cell damage

Scientists have identified a promising antiviral compound that specifically targets skin human papillomavirus (HPV) associated with skin cancer, providing hope for immunocompromised patients who are at an elevated risk of these persistent infections.

Small molecules designated as NSC51349 exhibit selective activity against skin infection types while keeping healthy cells free of harm, an important advantage to existing broad-spectrum methods and often cause significant toxicity.

The finding addresses key gaps in HPV treatment options. Although the vaccine effectively prevents certain mucosal HPV infections that cause cervical and head and neck cancers, there is no persistent infection with antiviral therapy, and the current vaccine does not protect against skin HPV types of the skin, thus affecting the skin primarily and possibly contributing to non-thyroid skin cancer.

Targeting viruses without damaging the host

“Inhibitors may represent novel HPV-specific antiviral drugs with great potential,” said Dr. Alla Piirsoo, a molecular virologist at the University of Tartu, Istonia, who led the study published in the Journal of Virology. “Difficulty” [HPV] Relying on a vaccine for the functional immune system Our strategies may benefit people with impaired immunity from the current treatment options are very limited. ”

The team used high-throughput screening to test over 1,500 chemicals from the National Cancer Institute’s diversity library against HPV type 5, a skin variant associated with increased risk of skin cancer. Their systematic approach identified two compounds with antiviral activity, but only NSC51349 proved safe against host cells while maintaining effective viral inhibition.

Laboratory studies show that NSC51349 has reduced 90% of HPV5 replication by 90% at concentrations that do not cause detectable damage to human cells. The selectivity of this compound is derived from its specific targeting of the viral E2 protein, which controls viral gene expression and genomic replication in the skin HPV type.

Mechanism reveals selective action

Late molecular modeling and experimental verification reveal the precise mechanism of action of NSC51349. This compound binds to specific amino acid residues on the HPV E2 protein – thionine 202, proline 203, threonine 473 and glutamate 474 – at key junctions between protein domains, but differs in mucosal changes.

This selective binding disrupts the transcriptional activity of the E2 protein without affecting its replication function, effectively sedimenting viral gene expression, including Oncogenes E6 and E7, which drive cell transformation. This approach represents a complex targeting strategy that can take advantage of fundamental differences between skin and mucosal HPV biology.

The main findings of the study include:

• Effectively inhibit HPV types 5, 8 and 38, with IC50 values ​​of approximately 4-8 µm
• No effect on mucosal HPV types 11, 16 and 18, demonstrating selectivity
• Preserve normal cell cycle, viability and differentiation of human keratinocytes
• Destruction of viral transcription while maintaining cellular transcription machinery

Address unmet medical needs

The potential of this compound goes beyond basic antiviral activity to address specific patient populations facing an elevated risk associated with HPV. Immunely low-functioning individuals (including organ transplant recipients, cancer patients receiving treatment, HIV-positive individuals, and people with rare genetic diseases) experience higher rates of persistent HPV infection and related complications.

Although the current HPV vaccine is very effective in preventing, it cannot treat existing infections and requires a functional immune system to produce a protective response. The direct antiviral mechanism of NSC51349 provides a complementary approach that can benefit patients regardless of their immune status.

The study also verified the activity of the compound in human primary keratinocytes (natural target cells infected by HPV). This demonstration in physiologically relevant cell types enhances the case of therapeutic development, because while showing hope in cancer cell lines, many antiviral candidates failed when tested in primary human cells.

From the laboratory to the clinic

The advantageous safety of the compound and the passage of the standard drug development filter can be well developed. Unlike many screening hits, NSC51349 passes a REO (rapid elimination) filter, has the desired drug-like properties and screens for the pan-assay interfering compounds, causing nonspecific effects.

Comparative studies with McAka fascial papillomavirus (as an animal model for human HPV studies) confirmed the selective activity of the compound against skin-type viruses while avoiding mucosal variants. This animal model system can facilitate preclinical development and ultimate clinical testing.

Researchers are now optimizing compound concentrations and planning animal studies to evaluate efficacy and safety in living systems. “If the compound works in an animal model, there can be ample evidence that it can develop into an effective antiviral treatment for HPV,” Piirsoo noted.

The success of animal studies will represent a significant advancement in the first HPV-specific antiviral therapy that could turn into a therapeutic option for ongoing skin HPV infections, which currently relies primarily on surgical clearance or destructive treatments with limited long-term effects.

Related