HBV Reverse Transcriptase

Hepatitis B virus (HBV) relies on its reverse transcriptase (RT) enzyme for viral DNA synthesis, a process essential for replication and involving multiple steps with distinct conformational requirements. All nucleoside analog-based antiviral drugs currently approved for chronic HBV infection target the RT, except interferon. The HBV RT uniquely initiates DNA synthesis via a protein priming mechanism, where the enzyme itself serves as a primer. This distinctive feature, along with other RT functions such as RNA recognition and packaging, presents multiple targets for antiviral intervention. Drugs like entecavir and tenofovir inhibit both protein priming and DNA elongation, while clevudine inhibits these stages non-competitively without incorporation into DNA, demonstrating that some nucleoside RT inhibitors can functionally mimic non-nucleoside RT inhibitors. These findings highlight the potential for developing novel NRTIs and NNRTIs targeting different stages of RT activity. Future curative strategies will likely require combination therapies incorporating RT inhibitors alongside agents targeting additional viral and host factors to achieve potent suppression and ultimately cure chronic HBV infection.