The dihydroquinolizinone compound RG7834 inhibits the polyadenylase function of PAPD5/7 and accelerates the degradation of matured HBV surface protein mRNA.

Hepatitis B virus (HBV) mRNA metabolism is dependent upon host proteins PAPD5 and PAPD7 (PAPD5/7). PAPD5/7 are cellular, non-canonical, poly(A) polymerases (PAP) whose main function is to oligoadenylate the 3' end of non-coding RNA (ncRNA) for exosome degradation. HBV seems to exploit these two ncRNA quality control factors for viral mRNA stabilization, rather than degradation. RG7834 is a small molecule compound that binds PAPD5/7 and inhibits HBV gene production in both tissue culture and animal study. We reported that RG7834 was able to destabilize multiple HBV mRNA species, ranging from the 3.5 kb pre-genomic/pre-core mRNAs to the 2.4/2.1 kb HBs mRNAs, except for the smallest 0.7 kb HBx mRNA. Compound induced HBV mRNA destabilization was initiated by a shortening of poly(A) tail followed by an accelerated degradation process in both the nucleus and cytoplasm. In cells expressing HBV mRNA, both PAPD5/7 were found to be physically associated with the viral RNA, and the polyadenylating activities of PAPD5/7 were susceptible to RG7834 repression in biochemical assay. Moreover, in PAPD5/7 double knockout cells, viral transcripts with regular length of poly(A) sequence could be initially synthesized but became shortened in hours suggesting that participation of PAPD5/7 in RNA 3' end processing, either during adenosine oligomerization or afterwards, is crucial for RNA stabilization.