Wednesday, October 9, 2024
10/9/2024
Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >250 million people worldwide and kills ~870,000 annually. Therapy primarily employs nucleos(t)ide analog drugs against viral DNA synthesis that often drive viremia below the detection limit. However, replication is not eliminated, and HBV resurges if drugs are withdrawn. Nevertheless, treatment cures up to 6% of patients, so more patients could be cured by suppressing HBV further. Reverse transcription requires the viral ribonuclease H (RNaseH) that destroys the RNA after it has been copied into DNA. Blocking the RNaseH prevents synthesis of viral genomes, including both the key nuclear cccDNA form of the genome and the DNA in virions. Drugs have not yet been designed against the RNaseH. We developed the first screening pipeline for HBV RNaseH inhibitors and found RNaseH >150 inhibitors that block HBV replication. The most effective is an N-hydroxypyridinedione (HPD) with an EC50 of 0.11 μM and a therapeutic index (TI, CC50/EC50) of 300. An HPD hit compound suppressed HBV viremia in mice with humanized livers. We also found that napthyridinones [NPTH, comprised of true napthyridinones (HNOs) and the closely related hydroxypyridopyrimidinones (HPPs)] inhibit HBV replication with EC50s as low as 0.95 μM and TIs up to 83. Achieving EC50s as low as 0.11 μM and TIs up to 350 after assessing only 51 HPDs, combined with good activity of the related NPTH chemotype, led Drs. Tavis (HBV virologist), Meyers, Zhan, and Zoidis and (medicinal chemists) to join forces to develop the HPDs and NPTHs into pre-clinical leads for novel HBV drugs. Aim 1. Lead optimization of HPD HBV inhibitors. We will synthesize up to 125 HPDs based on our existing structure-activity relationships (SAR) and evaluate their efficacy, cytotoxicity, and solubility. Aim 2. Hit-to-lead development of NPTH HBV inhibitors. We will synthesize up to 100 HNOs and 100 HPPs and evaluate their efficacy, cytotoxicity, and solubility. Aim 3. Assess specificity for HBV of the novel inhibitors. We will evaluate HPDs and NPTHs for induction of heteroduplex formation in HBV capsids and suppression of cccDNA formation. Synergy with other HBV drugs will be assessed. Selectivity will be measured against microbial pathogens and human metalloenzymes including RNaseH1. Aim 4. Evaluate pharmacological parameters for HPD and NPTH HBV inhibitors. We will assess stability, cellular permeability, plasma protein binding, pharmacokinetics, and toxicology of key inhibitors. Efficacy of the best compounds will be tested against HBV replication in HBV-infected mice carrying humanized livers. These studies will advanced HBV RNaseH inhibitors as first-in-mechanism and first-in-class HBV drug leads. The eventual anti-HBV RNaseH drugs are anticipated to be used in combination with nucleos(t)ide analogs to suppress HBV replication enough to clear HBV in many more patients than current therapies achieve.
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