龐西莫德通過抑制內體成熟來抑制乙型肝炎病毒感染

StephenW

Ponesimod suppresses hepatitis B virus infection by inhibiting endosome maturation
Yuzy Fauzyah  1 , Chikako Ono  2 , Shiho Torii  3 , Itsuki Anzai  4 , Rigel Suzuki  5 , Takuma Izumi  6 , Yuhei Morioka  7 , Yusuke Maeda  8 , Toru Okamoto  9 , Takasuke Fukuhara  10 , Yoshiharu Matsuura  11
Affiliations
Affiliations

    1
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    2
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    3
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    4
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    5
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    6
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    7
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    8
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    9
    Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    10
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].
    11
    Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan. Electronic address: [email protected].

    PMID: 33346055 DOI: 10.1016/j.antiviral.2020.104999

Abstract

The discovery of novel antivirals to treat hepatitis B virus (HBV) infection is urgently needed, as the currently available drugs mainly target viral proteins at replication step, whereas host factors also play significant roles in HBV infection. Although numerous studies have reported candidate drugs for HBV treatment, there remains a need to find a new drug that may target other steps of the HBV life cycle. In this study, by drug screening of a 533 G-protein-coupled receptors (GPCRs)-associated compound library, we identified ponesimod, a selective agonist of sphingosine-1-phosphate receptor 1 (S1P1), as a drug candidate for the suppression of HBV infection. However, the anti-HBV effect of ponesimod is independent of S1P1 and other sphingosine-1-phosphate receptors (S1PRs). Treatment with ponesimod at an early step of infection but not at a post-entry step significantly reduced the HBV relaxed circular DNA (rcDNA) level in a dose-dependent manner. Ponesimod treatment did not inhibit attachment, binding, or internalization of HBV particles via endocytosis through an interaction with sodium taurocholate cotransporting polypeptide (NTCP) or epidermal growth factor receptor (EGFR). Importantly, during the transportation of HBV particles to the nucleus, co-localization of HBV with early endosomes but not with late endosomes and lysosomes was induced by the treatment with ponesimod, suggesting that ponesimod interferes with the conversion of early endosomes to late endosomes without significant damage to cellular growth. Conclusion: Ponesimod is a promising anti-HBV drug targeting the endosome maturation of HBV. This finding can be applied to the development of novel antivirals that target the trafficking pathway of HBV particles.

Keywords: HBV; S1P(1) agonist; antiviral; endocytosis; endosome maturation; trafficking.

Copyright © 2020. Published by Elsevier B.V.

StephenW

龐西莫德通過抑制內體成熟來抑制乙型肝炎病毒感染
Yuzy Fauzyah 1，Chikako Ono 2，Shiho Torii 3，Itsuki Anzai 4，Rigel Suzuki 5，Takuma Izumi 6，Yohei Morioka 7，前田佑介8，岡本徹9，福原隆介10，松浦佳治11
隸屬關係
隸屬關係

    1個
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    2
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    3
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    4
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    5
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    6
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    7
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    8
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    9
    大阪大學微生物疾病研究所高級共同創造研究所，日本大阪565-0871。電子地址：[email protected]。
    10
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。
    11
    大阪大學微生物疾病研究所分子病毒學系，大阪，日本565-0871。電子地址：[email protected]。

    PMID：33346055 DOI：10.1016 / j.antiviral.2020.104999

抽象

迫切需要發現治療乙型肝炎病毒（HBV）感染的新型抗病毒藥，因為當前可用的藥物主要在復制步驟靶向病毒蛋白，而宿主因素在HBV感染中也起著重要作用。儘管許多研究已經報告了用於HBV治療的候選藥物，但是仍然需要尋找可能針對HBV生命週期其他步驟的新藥。在這項研究中，通過對533個G蛋白偶聯受體（GPCR）相關化合物庫的藥物篩選，我們確定了鞘氨醇-1-磷酸受體1（S1P1）的選擇性激動劑ponesimod作為抑製藥物的候選藥物乙肝病毒感染。但是，龐西莫德的抗HBV效應獨立於S1P1和其他1磷酸鞘氨醇受體（S1PRs）。在感染的早期階段但未在進入後階段進行龐西莫德治療，以劑量依賴性方式顯著降低了HBV鬆弛環狀DNA（rcDNA）的水平。泊尼西德治療不會通過與牛磺膽酸鈉共轉運多肽（NTCP）或表皮生長因子受體（EGFR）相互作用而通過內吞作用抑制HBV顆粒的附著，結合或內在化。重要的是，在將HBV顆粒轉運至細胞核期間，通過龐尼莫德治療可誘導HBV與早期內體共定位，而不與晚期內體和溶酶體共定位，這表明泊尼西莫干擾了早期內體向晚期內體的轉化，而沒有明顯影響。損害細胞生長。結論：龐西莫德是針對HBV內體成熟的有前途的抗HBV藥物。該發現可用於開發針對HBV顆粒運輸途徑的新型抗病毒藥。

關鍵字：HBV； S1P（1）激動劑；抗病毒物質;內吞內體成熟販運

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