Journal
MOLECULES
Volume 25, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/molecules25194434
Keywords
Hepatitis B virus; protein priming; epsilon RNA; minus strand DNA synthesis; 3; 7-dihydroxytropolones
Funding
- Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services
- National Institutes of Health [SC1GM111158, R01 AI122669]
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Initiation of protein-primed (-) strand DNA synthesis in hepatitis B virus (HBV) requires interaction of the viral reverse transcriptase with epsilon (epsilon), a cis-acting regulatory signal located at the 5' terminus of pre-genomic RNA (pgRNA), and several host-encoded chaperone proteins. Binding of the viral polymerase (P protein) to epsilon is necessary for pgRNA encapsidation and synthesis of a short primer covalently attached to its terminal domain. Although we identified small molecules that recognize HBV epsilon RNA, these failed to inhibit protein-primed DNA synthesis. However, since initiation of HBV (-) strand DNA synthesis occurs within a complex of viral and host components (e.g., Hsp90, DDX3 and APOBEC3G), we considered an alternative therapeutic strategy of allosteric inhibition by disrupting the initiation complex or modifying its topology. To this end, we show here that 3,7-dihydroxytropolones (3,7-dHTs) can inhibit HBV protein-primed DNA synthesis. Since DNA polymerase activity of a ribonuclease (RNase H)-deficient HBV reverse transcriptase that otherwise retains DNA polymerase function is also abrogated, this eliminates direct involvement of RNase (ribonuclease) H activity of HBV reverse transcriptase and supports the notion that the HBV initiation complex might be therapeutically targeted. Modeling studies also provide a rationale for preferential activity of 3,7-dHTs over structurally related alpha-hydroxytropolones (alpha-HTs).
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