In our previous blogs, we have introduced two HBV inhibitors. Today, I’d like to describe another small molecule compound BA-53038B that targets HBV core protein. A study from Xuexiang Zhang described BA-53038B as a HBV core protein allosteric modulator (CpAM). And BA-53038B modulates HBV capsid assembly in a distinct manner, with an EC50 value of 3.32 μM.

In the study, BA-53038B reduced the amount of fast migrating capsids and formed slow migrating capsids. Like other CpAMs, but distinct from viral DNA polymerase inhibitor ETV, BA-53083B reduced the amount of hypophosphorylated core protein, suggesting the inhibition of viral pgRNA encapsidation. Hence, these data suggested that BA-53083B treatment promoted the assembly of empty capsids with slow electrophoresis mobility.

In addition, BA-53038B treatment promoted the assembly of capsids with slow electrophoresis mobility, and reduced the amount of capsids with fast electrophoresis mobility. Therefore, like other type II CpAMs, BA-53038B inhibited pgRNA encapsidation into nucleocapsids and consequentially suppressed viral DNA replication. However, BA-53038B induced the assembly of structurally distinct empty capsids, as indicated by its slower electrophoresis mobility.

Interestingly, antiviral assay performed in HepAD38 cells indicated that BA-53038B completely lost activity to inhibit HBV replication, but demonstrated potent antiviral activities as observed in HepDES19 cells. These results imply that not only chirality but also polarity is important for modulators to interact with core protein dimers and disrupt nucleocapsid assembly, since 62031B (ClogP 2.62) is more polar than BA53038B (ClogP 4.15).

Lastly, the authors confirmed that BA-53038B modulates HBV capsid assembly by binding to the HAP pocket.

Zhang X, et al. Discovery of Novel Hepatitis B Virus Nucleocapsid Assembly Inhibitors. ACS Infect Dis. 2019 May 10;5(5):759-768.