Antiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus

Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >296 million people worldwide, including ∼850,000 in the USA, and kills 820,000 annually worldwide. Current nucleos(t)ide analogue (NA) or pegylated interferon α therapies do not eradicate the virus and would benefit from a complementary antiviral drug. We performed a preliminary screen of 28 dispirotripiperazines against HBV, identifying 9 hits with EC₅₀ of 0.7-25 μM. Compound 11826096 displays the most potent activity and represents a promising lead for future optimization. While the mechanism of action is unknown, preliminary assays limit possible targets to activities involved in RNA accumulation, translation, capsid assembly, and/or capsid stability. In addition, we built machine learning models to determine if they were able to predict the activity of this series of compounds. The novelty of these molecules indicated they were outside of the applicability domain of these models.