The assembly of hepatitis B virus (HBV) core proteins (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid assembly modulators (CAMs) induce the formation of empty-capsid or aberrant-capsid devoid of pregenomic RNA (pgRNA) and finally block rcDNA neosynthesis and virion progeny. In this study, novel CAMs JNJ-827 and JNJ-890, were found to be potent inhibitors of HBV replication with a respective half maximal effective concentration of 4.7 and 66 nM in HepG2.117 cells. Antiviral profiling in differentiated HepaRG (dHepaRG) cells and primary human hepatocytes (PHH) revealed that these compounds efficiently inhibited HBV replication, as well as de novo establishment of cccDNA. In addition to these two known effects of CAMs, we observed for the first time that a CAM, here JNJ-827, when added post-infection for a short-term period, significantly reduced HBeAg secretion without affecting the levels of cccDNA amount, transcription, and HBsAg secretion. This inhibitory activity resulted from a direct effect of JNJ-827 on HBeAg biogenesis. In a long-term treatment condition using persistently infected dHepaRG cells, JNJ-827 and JNJ-890 reduced HBsAg, concomitantly to a decrease in viral total RNA and pgRNA levels. Altogether, these data demonstrate that some CAMs could interfere with multiple functions of HBc in the viral life cycle.
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