宿主RNA質量控製作為乙型肝炎抗病毒靶標

StephenW

Host RNA quality control as a hepatitis B antiviral target
Timothy M Block  1 , John A T Young  2 , Hassan Javanbakht  3 , Michael J Sofia  4 , Tianlun Zhou  5
Affiliations
Affiliations

    1
    Baruch S. Blumberg Institute, Doylestown, PA, 18902. Electronic address: [email protected].
    2
    Roche Pharma Research & Early Development, Roche Innovation Center Basel, F.Hoffmann-La Roche Ltd, Basel Switzerland. Electronic address: [email protected].
    3
    SQZ Biotechnologies, 200 Arsenal Yards Blvd, Suite 210 Watertown, MA 02472, Hassan. Electronic address: [email protected].
    4
    Arbutus Biopharma, Inc, 701 Veterans Circle Warminster, PA 18974. Electronic address: [email protected].
    5
    Baruch S. Blumberg Institute, Doylestown, PA, 18902. Electronic address: [email protected].

    PMID: 33242518 DOI: 10.1016/j.antiviral.2020.104972

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.

Keywords: Dihroxyquinolines; PAP D5; PAPD7; RNA; Therapeutics; hepatitis b.

Copyright © 2020. Published by Elsevier B.V.

StephenW

宿主RNA質量控製作為乙型肝炎抗病毒靶標
蒂莫西·M街區1，約翰·阿特·揚2，哈桑·Javanbakht 3，邁克爾·索菲亞4，週天倫
隸屬關係
隸屬關係

    1個
    Baruch S. Blumberg研究所，賓夕法尼亞州Doylestown，18902年。電子地址：[email protected]。
    2
    瑞士巴塞爾F.Hoffmann-La Roche有限公司，巴塞爾羅氏創新中心，羅氏製藥研究與早期開發。電子地址：[email protected]。
    3
    SQZ Biotechnologies，200 Arsenal Yards Blvd，Suite 210 Watertown，MA 02472，Hassan。電子地址：[email protected]。
    4
    Arbutus Biopharma，Inc，701 Veterans Circle Warminster，PA18974。電子地址：[email protected]。
    5
    Baruch S. Blumberg研究所，賓夕法尼亞州Doylestown，18902年。電子地址：[email protected]。

    PMID：33242518 DOI：10.1016 / j.antiviral.2020.104972

抽象

用口服的小分子二羥基喹啉（DHQ）抑制宿主RNA聚腺苷酸化聚合酶PAPD5和PAPD7（PAPD5 / 7）會導致乙型肝炎病毒（HBV）RNA的快速選擇性降解，從而降低病毒基因產物的量。 DHQ是同類研究中的佼佼者，可能代表了全新的HBV抗病毒藥物類別。 PAPD5和PAPD7是非規範的，特定於細胞的，聚腺苷酸化聚合酶，也分別稱為末端核苷酸轉移酶4B和4A（TENT4B / A）。它們參與劣質細胞轉錄本（主要是非編碼RNA）的降解以及轉錄本亞組的成熟。它們似乎在屏蔽某些mRNA降解中也起著作用。 DHQ的研究結果以及其他最近的發現提供了證據，證明細胞“ RNA質量控制”途徑的PAPD5 / 7臂的抑制會導致（而不是增加）大量的減少（而不是增加）。組織培養和動物模型中的HBV基因組前，核心前和HBsAg mRNA水平也是如此。在這篇綜述中，我們將簡要討論對新的HBV治療藥物的需求，並提供有關HBV轉錄的背景。我們還討論了宿主轉錄本的細胞降解，因為它涉及乾擾這些過程的新的抗HBV藥物家族。最後，由於HBV mRNA成熟似乎對肝細胞中PAPD5 / 7的抑製作用選擇性敏感，因此我們討論了靶向宿主RNA“質量控制”作為抗病毒策略的可能性。

關鍵字：二羥基喹啉； PAP D5； PAPD7； RNA;療法;乙肝

版權所有©2020。由Elsevier B.V.發布。

newchinabok

StephenW 发表于 2020-11-27 19:49
宿主RNA質量控製作為乙型肝炎抗病毒靶標
蒂莫西·M街區1，約翰·阿特·揚2，哈桑·Javanbakht 3，邁克爾· ...

一鸟在手，胜过十鸟在林。免疫药就剩下apg1387和治疗性疫苗tg101了，剩下最后的希望了，明年就会有答案，如果不成功，10年也没戏