RG7834 is a potent, orally bioavailable small‐molecule inhibitor of hepatitis B virus (HBV) gene expression that belongs to the dihydroquinolizinone (DHQ) chemical class and uniquely blocks production of both viral DNA and antigens. In this study, we used DHQ compounds as tools in a compound‐based adaptation version of the yeast three‐hybrid screen to identify the cognate cellular protein targets, the non‐canonical poly(A) RNA polymerase associated domain containing proteins 5 and 7 (PAPD5 and PAPD7). Interaction with RG7834 was mapped to the catalytic domains of the two cellular enzymes. The role of PAPD5 and PAPD7 in HBV replication was confirmed by oligonucleotide‐mediated knockdown studies that phenocopied the result seen with RG7834‐treated HBV‐infected hepatocytes. The greatest effect on HBV gene expression was seen when PAPD5 and PAPD7 mRNAs were simultaneously knocked down, suggesting that the two cellular proteins play a redundant role in maintaining HBV mRNA levels. In addition, as seen previously with RG7834 treatment, PAPD5 and PAPD7 knockdown led to destabilization and degradation of HBV mRNA without impacting production of viral RNA transcripts. Conclusion: We identify PAPD5 and PAPD7 as cellular host factors required for HBV RNA stabilization and as therapeutic targets for the HBV cure.
Chronic
hepatitis B virus (HBV) infection is a serious public health
burden, and current therapies cannot achieve satisfactory cure rate.
There are high unmet medical needs of novel therapeutic agents with
differentiated mechanism of action (MOA) from the current standard
of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical
series, is a first-in-class highly selective and orally bioavailable
HBV inhibitor which can reduce both viral antigens and viral DNA with
a novel mechanism of action. Here we report the discovery of RG7834
from a phenotypic screening and the structure–activity relationship
(SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV
but not other DNA or RNA viruses in a virus panel screening. Both
in vitro and in vivo profiles of RG7834 are described herein, and
the data support further development of this compound as a chronic
HBV therapy.
A cascade of tetrahydrofurans: A one‐pot cascade reaction for the preparation of fully substituted tetrahydrofurans from aryldiazoacetates and allyl alcohols is reported. Rh‐catalyzed diazo decomposition of diazoacetates 1 with a secondary alcohols 2 gave an OH insertion product with excellent diastereoselectivity. Subsequent intramolecular Michael‐type addition produced the desired tetrahydrofurans 3 with excellent stereoselective control.
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