Shedding light on RNaseH: a promising target for hepatitis B virus (HBV)

Edwards, Tiffany C.; Ponzar, Nathan L.; Tavis, John E.

doi:10.1080/14728222.2019.1619697

Cited by 13 publications

(9 citation statements)

References 16 publications

(22 reference statements)

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“…As with retroviral RTs, degradation of the RNA/DNA HBV replication intermediate is catalyzed by its RT-associated RNase H domain. Although no inhibitor of HIV-1 RT RNase H function has advanced to the clinic, intense efforts over almost 2 decades have made a plethora of compounds available for testing its HBV counterpart [ 9 , 10 ]. Following reports that the natural product α-hydroxytropolone (α-HT), β-thujaplicinol [ 11 ] inhibits HBV replication by sequestering the catalytic Mg ++ in the RNase H active site [ 12 ], modified α-HTs [ 13 ], 2-hydroxyisoquinoline-1,3(2H,4H)-diones [ 14 ] and N -hydroxypyridinediones, have emerged as a new class of RNase H inhibitors [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis

et al. 2020

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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 (ε), 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 ε 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 ε 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 α-hydroxytropolones (α-HTs).

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Section: Introductionmentioning

confidence: 99%

3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis

et al. 2020

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“…However, inhibiting one or more mono-or di-metalloenzymes needed for viral replication by chelating their active site cations is a likely mechanism. The rationale for implicating metal chelation comes from the compound structures and their known activities against HIV and presumed activity against HBV [10][11][12]. The αHTs and HPDs have metal chelating tridents suitable for binding to the Mg++ ions in di-metalloenzyme active sites, and the αHTs are known to work by this mechanism against the HIV ribonuclease H and/or integrase [11,15].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibiting viral endonucleases can block viral replication, as has been shown for the HIV integrase [10], the HIV ribonuclease H [11], the Hepatitis B Virus (HBV) ribonuclease H [12], and the influenza virus cap-snatching enzyme [13,14]. The most common mode of inhibition is for small molecules to chelate the Mg++ ions in viral nuclease active sites, with specificity and affinity modulated by additional contacts between the inhibitors and the enzymes [15-17], and sometimes also by contacts with the nucleic acid substrate [18].…”

Section: Introductionmentioning

confidence: 99%

Metal Coordinating Inhibitors of Rift Valley Fever virus Replication

Geerling

Murphy

Stone

et al. 2022

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Rift Valley Fever Virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the Bunyavirales order, and replication of these viruses depends on the viral endonuclease activity of the viral L protein. Screening for RVFV replication inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 31 novel RVFV inhibitors with selective indexes from 5 – 402 and 50% effective concentrations of 0.54 – 56 µM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against another Bunyavirus, La Crosse Virus (LACV). Conservation of the enzymatic activity such as the cap-snatching mechanism among the Bunyavirales implies that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes hold potential for development into treatments for related pathogens, including Hantaan Virus, Severe fever with thrombocytopenia syndrome virus, Crimean-Congo Hemorrhagic Fever Virus, and LACV. Keywords: Rift Valley Fever Virus 1, La Crosse virus 2, Cap-snatching endonuclease 3, Replication inhibitors 4, α-Hydroxytropolones 5, N-Hydroxypyridinediones 6.

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“…However, the RNase H represents a target definitely worth to be further explored. It could furnish an alternative therapeutic option not only against HIV infection but also to treat Hepatitis B virus (HBV) infection, which is another global health problem for whicH-News drugs are urgently needed [60].…”

Section: Discussionmentioning

confidence: 99%

1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity

et al. 2020

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Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of action. In this context, the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H), which is one of the few HIV-1 encoded enzymatic function still not targeted by any current drug, can be considered as an appealing target. In this work, we repurposed in-house anti-influenza derivatives based on the 1,2,4-triazolo[1,5-a]-pyrimidine (TZP) scaffold for their ability to inhibit HIV-1 RNase H function. Based on the results, a successive multi-step structural exploration around the TZP core was performed leading to identify catechol derivatives that inhibited RNase H in the low micromolar range without showing RT-associated polymerase inhibitory activity. The antiviral evaluation of the compounds in the MT4 cells showed any activity against HIV-1 (IIIB strain). Molecular modelling and mutagenesis analysis suggested key interactions with an unexplored allosteric site providing insights for the future optimization of this class of RNase H inhibitors.

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Shedding light on RNaseH: a promising target for hepatitis B virus (HBV)

Cited by 13 publications

References 16 publications

3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis

3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis

Metal Coordinating Inhibitors of Rift Valley Fever virus Replication

1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity

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