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Abstract Details
Host RNA quality control as a hepatitis B antiviral target
Antiviral Res. 2020 Nov 23;104972. doi: 10.1016/j.antiviral.2020.104972.Online ahead of print.
Timothy M Block1, John A T Young2, Hassan Javanbakht3, Michael J Sofia4, Tianlun Zhou5
Author information
1Baruch S. Blumberg Institute, Doylestown, PA, 18902. Electronic address: tim.block@bblumberg.org.
2Roche Pharma Research & Early Development, Roche Innovation Center Basel, F.Hoffmann-La Roche Ltd, Basel Switzerland. Electronic address: john.young.jy3@roche.com.
3SQZ Biotechnologies, 200 Arsenal Yards Blvd, Suite 210 Watertown, MA 02472, Hassan. Electronic address: javanbakht@SQZbiotech.com.
4Arbutus Biopharma, Inc, 701 Veterans Circle Warminster, PA 18974. Electronic address: msofia@arbutusbio.com.
5Baruch S. Blumberg Institute, Doylestown, PA, 18902. Electronic address: tianlun.zhou@bblumberg.org.
Abstract
Inhibition of the host RNA polyadenylating polymerases, PAPD5 and PAPD7 (PAPD5/7), with dihydroxyquinoline (DHQ), a small orally available, molecule, results in a rapid and selective degradation of hepatitis B virus (HBV) RNA, and hence reduction in the amounts of viral gene products. DHQ, is a first in class investigational agent and could represent an entirely new category of HBV antivirals. PAPD5 and PAPD7 are non-canonical, cell specified, polyadenylating polymerases, also called terminal nucleotidyl transferases 4B and 4A (TENT4B/A), respectively. They are involved in the degradation of poor-quality cell transcripts, mostly non-coding RNAs and in the maturation of a sub-set of transcripts. They also appear to play a role in shielding some mRNA from degradation. The results of studies with DHQ, along with other recent findings, provide evidence that repression of the PAPD5/7 arm of the cell "RNA quality control" pathway, causes a profound (multi-fold) reduction rather than increase, in the amount of HBV pre-genomic, pre-core and HBsAg mRNA levels in tissue culture and animal models, as well. In this review we will briefly discuss the need for new HBV therapeutics and provide background about HBV transcription. We also discuss cellular degradation of host transcripts, as it relates to a new family of anti-HBV drugs that interfere with these processes. Finally, since HBV mRNA maturation appears to be selectively sensitive to PAPD5/7 inhibition in hepatocytes, we discuss the possibility of targeting host RNA "quality control" as an antiviral strategy.