Efficient pyrophosphorolysis by a hepatitis B virus polymerase may be a primer-unblocking mechanism.

摘要: Effective antiviral agents are thought to inhibit hepatitis B virus (HBV) DNA synthesis irreversibly by chain termination because reverse transcriptases (RT) lack an exonucleolytic activity that can remove incorporated nucleotides. However, since the parameters governing this inhibition poorly defined, fully delineating catalytic mechanism of HBV-RT promises facilitate development drugs for treating chronic HBV infection. To end, pyrophosphorolysis and pyrophosphate exchange, two nonhydrolytic RT activities result in removal newly nucleotides, were characterized using endogenous avian replication complexes assembled vivo. Although these presumed be physiologically irrelevant every polymerase examined, efficiency with which they catalyzed strongly suggests it is first known catalyze reactions under replicative conditions. The ability nucleotides during has important biological clinical implications: may serve a primer-unblocking function Analysis on chain-terminated revealed potent anti-HBV drug β-l-(−)-2′,3′-dideoxy-3′-thiacytidine (3TC) was difficult pyrophosphorolysis, contrast ineffective terminators such as ddC. This disparity account strong efficacy 3TC versus pyrophosphorolytic therefore novel determinant efficacy, could target future therapy. inhibitory effect cytoplasmic concentrations viral also partly apparent slow rate genome replication.