Figure 2.

Schematic diagram of HBV infection pathway. The pathway of infection involves NTCP receptor-mediated uptake of HBV particles into hepatocytes, followed by controlled endo-osmolysis that enables the nuclear capsid to enter the cell nucleus where rcDNA can be processed into fully functional cccDNA. This is either propagated into pgRNA for new virus particle production or integrated into host cell chromosomes. The pgRNA has multiple functions to initiate the re-synthesis of viral DNA, plus originate pre-C mRNA and all other sub viral mRNAs that code for all the main viral proteins. In the case of the first function, pgRNA is encapsulated with viral DNA polymerase (Pol) using HBc proteins to form immature nucleocapsids within which pgRNA is subject to reverse transcription by Pol to form complementary single-stranded DNA [negative (anti-sense)]. This is then nicked during reverse transcription as positive (sense) strand DNA is being partially generated and rcDNA reformed. Packaged rcDNA in mature nucleocapsid is then processed through the endoplasmic reticulum (ER) of a host hepatocyte leading to exocytosis of mature infectious HBV viral particles. The different classes of active pharmaceutical agents (APIs) that can modulate the infection cycle are as follows: entry inhibitors that act on NTCP mediated entry; anti-cccDNA agents such as HBx inhibitors, transcription activator-like effector nucleases (TALENs), zinc finger nucleases (ZFNs), and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated endonuclease (Cas); anti-mRNA agents such as RNA interference (RNAi) effectors, RNA destabilizers, and antisense oligonucleotides (ASOs)–locked nucleic acids (LNAs); anti-nucleocapsid assembly agents such as core protein allosteric modulators (CpAMs); reverse transcriptase inhibitors such as nucleoside/nucleotide analogues (NUCs) or RNaseH inhibitors; release inhibitors including nucleic acid polymers (NAPs).