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Soo Park, MD
Soo Park, MD
Posted: Friday, July 18, 2025
Alla Piirsoo, PhD, of the University of Tartu, Estonia, and colleagues identified a passively cell-permeable small-molecule inhibitor—5,7-dimethoxy-2-pyridin-3-ylchromen-4-one (NSC51349)—that targets cancer-associated human papillomavirus (HPV) 5 replication by inhibiting E2-dependent transcription. Their findings, which were published in the Journal of Virology, also open the possibility of optimizing the structure of this lead compound to enhance its efficacy and facilitate the development of novel antiviral drugs.
“To date, there are no HPV-specific antivirals, and vaccines designed for mucosal HPV types are ineffective against cutaneous HPV variants and ongoing infections,” the investigators commented. In an American Society for Microbiology press release, Dr. Piirsoo added, “Unlike [HPV] vaccines, which rely on the functioning immune system, our strategy could benefit people with compromised immunity who currently have very limited therapeutic options.” This group is especially vulnerable to HPV-associated cancers.
Upon performing high-throughput screening using the Diversity Set VI library of small-molecule compounds, the investigators identified NSC51349 as a potent inhibitor of oncogenic cutaneous HPV5 replication in U2OS cells. NSC51349 demonstrated selective inhibition of HPV5 genome replication in human primary keratinocytes (half maximal inhibitory concentration [IC50] ≈ 4 µM); it appeared to do so without exerting adverse effects on cell viability, growth, or differentiation. The compound was also found to inhibit the replication of other cutaneous HPV types, including HPV8 and HPV38, as well as Macaca fascicularis papillomavirus type 1 genomes.
Mechanistically, NSC51349-mediated inhibition appeared to involve the suppression of the viral protein E2 transcriptional activity. Molecular docking predicted that NSC51349 interacts with the HPV5 E2 protein by binding to two key amino acid residue pairs: threonine 202/proline 203, located at the junction of the transactivation domain and hinge region; and threonine 473/glutamate 474, situated at the DNA-binding domain.
“If the compound works in [an] animal model, it would be strong evidence that it could be developed into an effective antiviral treatment for HPVs,” Dr. Piirsoo concluded.
Disclosure: The study authors reported no conflicts of interest.
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