五環戊烷型樺木蛋白衍生的三萜類化合物中的選擇性乙型和

StephenW

Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
Michael Kirstgen  1 , Kira Alessandra Alicia Theresa Lowjaga  1 , Simon Franz Müller  1 , Nora Goldmann  2 , Felix Lehmann  2 , Sami Alakurtti  3   4 , Jari Yli-Kauhaluoma  3 , Dieter Glebe  2 , Joachim Geyer  5
Affiliations
Affiliations

    1
    Biomedical Research Center Seltersberg (BFS), Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Schubertstr. 81, 35392, Giessen, Germany.
    2
    National Reference Center for Hepatitis B Viruses and D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, 35392, Giessen, Germany.
    3
    Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, P.O. Box 56, 00014, Helsinki, Finland.
    4
    VTT Technical Research Centre of Finland, Biologinkuja 7, P.O. Box 1000, 02044, Espoo, Finland.
    5
    Biomedical Research Center Seltersberg (BFS), Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Schubertstr. 81, 35392, Giessen, Germany. [email protected].

    PMID: 33303817 DOI: 10.1038/s41598-020-78618-2

Free article
Abstract

Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP's physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure-activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.

StephenW

五環戊烷型樺木蛋白衍生的三萜類化合物中的選擇性乙型和丁型肝炎病毒進入抑製劑
Michael Kirstgen 1，Kira Alessandra Alicia Theresa Lowjaga 1，Simon FranzMüller1，Nora Goldmann 2，Felix Lehmann 2，Sami Alakurtti 3 4，Jari Yli-Kauhaluoma 3，Dieter Glebe 2，Joachim Geyer 5
隸屬關係
隸屬關係

    1個
    賈斯圖斯·利比格大學吉森分校獸醫學系藥理學和毒理學研究所塞特斯貝格（BFS）生物醫學研究中心。 81，35392，吉森，德國。
    2
    吉森賈斯圖斯·利比格大學醫學病毒研究所，國家乙型肝炎病毒和丁型肝炎病毒參考中心，德國吉森，35392。
    3
    赫爾辛基大學藥學院藥物化學與技術系藥物研究計劃，Viikinkaari 5 E，P.O.郵箱56 00014，芬蘭赫爾辛基。
    4
    芬蘭VTT技術研究中心，Biologinkuja 7，P.O。 Box 1000，02044，Espoo，Finland。
    5
    賈斯圖斯·利比格大學吉森分校獸醫學系藥理學和毒理學研究所塞特斯貝格（BFS）生物醫學研究中心。 81，35392，吉森，德國。 [email protected]。

    PMID：33303817 DOI：10.1038 / s41598-020-78618-2

免費文章
抽象

當前針對乙型和丁型肝炎病毒（HBV / HDV）感染的治療選擇僅具有有限的療效。 Na + /牛磺膽酸鹽共轉運多肽（NTCP）在2012年被鑑定為兩種病毒的高親和力肝受體，可實現基於靶標的HBV / HDV細胞進入抑製劑的開發。許多研究已經確定了合適的NTCP抑製劑。但是，它們中的大多數會干擾NTCP作為肝膽汁酸轉運蛋白的生理功能。為克服此缺點，本研究旨在尋找能特異性阻斷HBV / HDV與NTCP結合而不影響其轉運蛋白功能的化合物。概念化了一種新穎的檢測方法，可以同時進行篩選。病毒與NTCP的結合（通過大HBV / HDV包膜蛋白的preS1衍生肽的結合來測量）和通過NTCP的膽汁酸轉運。隨後通過使用NTCP-HepG2細胞的體外HDV感染研究驗證了命中。樺木衍生的五環環戊烷型三萜類樺木白蛋白的衍生物顯示出明顯的NTCP抑制能力和對NTCP病毒受體功能的選擇性。在這兩個方面表現最好的化合物分別是2、6、19和25。總的來說，甜菜鹼衍生物顯示出明確的結構-活性關係，可有效和選擇性地抑制NTCP的HBV / HDV病毒受體功能，而不會影響其生理膽汁酸轉運功能因此是有前途的候選藥物。

StephenW

https://www.nature.com/articles/s41598-020-78618-2.pdf