RXR agonist S169 inhibits HBV/HDV entry in vitro by disrupting KIF4-dependent NTCP trafficking

Area of Science:

• Hepatology
• Virology
• Drug Discovery

Background:

• Chronic hepatitis B (HBV) and hepatitis D (HDV) infections are significant global health concerns lacking curative treatments.
• Kinesin Family Member 4 (KIF4) regulates NTCP, the entry receptor for HBV/HDV.
• Bexarotene, an RXR agonist, inhibits HBV/HDV but has poor clinical properties.

Purpose of the Study:

• To identify novel Retinoid X Receptor (RXR) modulators as potential antiviral agents for HBV/HDV.
• To evaluate the efficacy and mechanism of the RXR agonist S169 against HBV/HDV entry.

Main Methods:

• Screening of chemically diverse RXR modulators.
• In vitro studies using primary human hepatocytes (PXB) infected with HBV/HDV.
• Analysis of viral markers (HBsAg, HBeAg, cccDNA, RNA, DNA) and NTCP surface levels.
• Assessment of cytotoxicity and bile acid transport.

Main Results:

• S169 identified as a potent inhibitor of HBV/HDV entry into hepatocytes without cytotoxicity.
• S169 reduced viral markers, including secreted antigens and intracellular viral DNA.
• Mechanism involves suppression of FOXM1-mediated KIF4 expression, decreasing NTCP surface levels and preS1 peptide binding.
• S169 demonstrated favorable pharmacokinetic properties and reduced toxicity compared to Bexarotene.

Conclusions:

• S169 is a novel HBV/HDV entry inhibitor with promising therapeutic potential.
• Its mechanism targets KIF4-mediated NTCP transport, offering a new antiviral strategy.
• S169 represents a potential seed for developing orally available antiviral drugs for HBV and HDV.