Baruch S. Blumberg Institute, Doylestown, PA, 18902, USA.
Roche Pharma Research & Early Development, Roche Innovation Center Basel, F.Hoffmann-La Roche Ltd, Basel, Switzerland.
Antiviral Res. 2021 Feb;186:104972. doi: 10.1016/j.antiviral.2020.104972. Epub 2020 Nov 24.
Inhibition of the host RNA polyadenylating polymerases, PAPD5 and PAPD7 (PAPD5/7), with dihydroquinolizinone, 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.
抑制宿主 RNA 多聚腺苷酸化聚合酶 PAPD5 和 PAPD7（PAPD5/7），使用二氢喹啉酮，一种小的口服可用的分子，导致乙型肝炎病毒（HBV）RNA 的快速和选择性降解，从而减少病毒基因产物的数量。DHQ 是一种首创的研究药物，可能代表一种全新的乙型肝炎抗病毒药物类别。PAPD5 和 PAPD7 是非经典的、细胞特异性的多聚腺苷酸化聚合酶，也分别称为末端核苷酸转移酶 4B 和 4A（TENT4B/A）。它们参与劣质细胞转录物的降解，主要是非编码 RNA，并参与一组转录物的成熟。它们似乎也在保护一些 mRNA 免受降解方面发挥作用。DHQ 的研究结果以及其他最近的发现提供了证据，表明抑制细胞“RNA 质量控制”途径的 PAPD5/7 臂会导致 HBV 前基因组、前核心和 HBsAg mRNA 水平在组织培养和动物模型中大量（多倍）降低，而不是增加。在这篇综述中，我们将简要讨论对新型乙型肝炎治疗药物的需求，并提供乙型肝炎转录的背景信息。我们还讨论了与干扰这些过程的新型抗乙型肝炎药物相关的宿主转录物的细胞降解。最后，由于 HBV mRNA 成熟似乎在肝细胞中对 PAPD5/7 抑制具有选择性敏感性，我们讨论了将宿主 RNA“质量控制”作为抗病毒策略的可能性。
