HBV replication inhibitors

Abstract

Chronic Hepatitis B Virus infections afflict >250 million people and kill nearly 1 million annually. Current non-curative therapies are dominated by nucleos(t)ide analogs (NAs) that profoundly but incompletely suppress DNA synthesis by the viral reverse transcriptase. Residual HBV replication during NA therapy contributes to maintenance of the critical nuclear reservoir of the HBV genome, the covalently-closed circular DNA, and to ongoing infection of naive cells. Identification of next-generation NAs with improved efficacy and safety profiles, often through novel prodrug approaches, is the primary thrust of ongoing efforts to improve HBV replication inhibitors. Inhibitors of the HBV ribonuclease H, the other viral enzymatic activity essential for viral genomic replication, are in preclinical development. The complexity of HBV's reverse transcription pathway offers many other potential targets. HBV's protein-priming of reverse transcription has been briefly explored as a potential target, as have the host chaperones necessary for function of the HBV reverse transcriptase. Improved inhibitors of HBV reverse transcription would reduce HBV's replication-dependent persistence mechanisms and are therefore expected to become a backbone of future curative combination anti-HBV therapies.

Keywords: Chronic hepatitis B; Hepatitis B virus; Nucleos(t)ide analogs; Reverse transcriptase inhibitors; Ribonuclease H inhibitors.

Fig. 1.. HBV reverse transcription.

The HBV reverse transcription pathway is shown with the nucleic acids in an extended form for clarity. In capsids, the three strand transfer reactions are promoted by specific conformations of the nucleic acids. Red, RNA; Blue, DNA; Green, protein. R, the long terminal repeat in the pregenomic RNA; r, the shorter terminal repeat in the minus-polarity DNA strand. 1, direct repeat 1; 2, direct repeat 2. Modified from (Tavis et al., 1994).

Fig. 2.. Nucleos(t)ide analogs approved for treatment of HBV infections as DNA polymerase inhibitors.

Trade names and developers are indicated for each drug.

Fig. 3.. New nucleos(t)ide analog prodrugs recently published or in clinical development for treating HBV infections.

Fig. 4.. Example HBV ribonuclease H inhibitors.

The HID, HPD, HNO, and αHT chemotypes are indicated.