CN114945361A - Fxr激动剂在治疗丁型肝炎病毒感染中的用途 - Google Patents
Fxr激动剂在治疗丁型肝炎病毒感染中的用途 Download PDFInfo
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- CN114945361A CN114945361A CN202180009266.0A CN202180009266A CN114945361A CN 114945361 A CN114945361 A CN 114945361A CN 202180009266 A CN202180009266 A CN 202180009266A CN 114945361 A CN114945361 A CN 114945361A
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Abstract
本发明涉及法尼醇X受体(FXR)激动剂在治疗丁型肝炎感染中的用途。
Description
技术领域
本发明涉及医学、尤其是肝脏病学和病毒学领域,更特别涉及丁型肝炎病毒(HDV)感染的治疗。
背景技术
丁型肝炎病毒(HDV)感染是慢性病毒性肝炎的最严重形式,因其迅速发展为与肝脏相关的死亡和肝细胞癌。世界卫生组织(WHO)估计有一千五百万到两千万人感染HDV(www.who.int/en/news-room/fact-sheets/detail/hepatitis-d)。最近对HDV携带的荟萃分析表明低估了丁型肝炎的患病率;事实上,血清阳性率可能高达全球人口的0.98%和全球慢性乙型肝炎患者的10.58%(Chen H-Y等,Gut 2019;68:512–521)。在没有特异性抗HDV疗法的情况下,目前的指导方针一般推荐皮下注射聚乙二醇化干扰素α-2a(PEG-IFN-α2a),这是一种非特异性免疫刺激剂,颇具毒性,患者承受度差。它经常与控制HBV病毒血症的核苷类似物一起使用。持续病毒学应答的总体率低。事实上,据报道治疗的应答率为约25%,并且停止治疗后复发水平高。因此,对于治疗HDV感染的新治疗剂和策略存在未满足的需求。然而,在为这些患者开发治疗剂上存在一些困难。
HDV基因组是负极性的单链的RNA(≈1700个核苷酸),含有单个开放阅读框,其编码两种病毒蛋白:小δ和大δ抗原(HDAg-S和HDAg-L)。HDV RNA基因组的复制在受感染细胞的细胞核中进行,并通过滚环机制发生,随后被内源性核酶切割和连接,从而形成反基因组环状单体。由这些环状反基因组单体,以相同的机制产生新的基因组环状RNA单体。人们认为HDV在基因组复制步骤期间劫持了DNA依赖性的宿主RNA聚合酶。HDV至少使用RNA聚合酶II进行病毒mRNA的复制和转录,但也提示了RNA聚合酶I和III的作用(Mentha N等,J AdvRes.2019年5月;17:3–15)。在此过程期间,还合成了病毒线性mRNA,导致HDAg-S和HDAg-L的合成。与HDAg-S(195个氨基酸)相比,HDAg-L(214个氨基酸)在其C端含有一个19-20个氨基酸的额外结构域,这是由对应于HDAg-S基因终止密码子位置处的反基因组HDV RNA的ADAR-1介导的RNA编辑产生的(Wong SK,Lazinski DW.Proc Natl Acad Sci U S A.2002年11月12日;99(23):15118–23)。HDAg-S在复制步骤期间参与HDV聚积。特别是,HDAg-S被认为与许多细胞蛋白相互作用(已鉴定的相互作用物多于100种),并与参与转录调控的细胞蛋白例如阴阳蛋白1(YY1)、组蛋白乙酰转移酶(HAT)、p300Creb结合蛋白(p300/CBP)和选择性因子1(SL1)相结合存在于核复合物中,该复合物属于RNA聚合酶I的起始前复合物(Huang W-Hetal.J Virol.2008年8月;82(15):7313–24;Li Y-J等,J Virol.2006年7月;80(13):6478–86)。还描述了HDAg-S与细胞组蛋白H1.4的相互作用对病毒复制具有后果(Lee C-Z,Sheu J-C.Virology.2008年5月25日;375(1):197–204)。HDAg-S主要参与复制步骤,而HDAg-L对病毒体出芽至关重要。HDAg-L中19-20个氨基酸的附加结构域含有CXXX-box基序,它是细胞法尼基转移酶的底物,该酶在该CXXX-box的半胱氨酸上添加法尼基基团。该法尼基化过程被证明对病毒体组装至关重要(Glenn J等,Science.1992年5月29日;256(5061):1331–3)。在此步骤期间,HDV劫持HBV表面抗原供自己使用,并分泌可以传播或维持感染的传染性HDV病毒体。HBV和HDV病毒体含有相同的包膜蛋白,从体液应答的角度来看是无法区分的。因此,HBV和HDV共享相同的进入受体,即牛磺胆酸钠共转运多肽(NTCP),它是肝细胞基侧膜处的胆汁酸(BA)主要转运蛋白(Yan H等,eLife[互联网].2012年11月13日[2019年9月3日引用];1。可得自:https://elifesciences.org/articles/00049)。由于这种病毒共生,HDV传播通常通过HBV合并感染(co-infection)或重叠感染(super-infection)发生。然而,除了HB抗原(HBAg)在肝细胞进入中的关键作用外,上述HDV生命周期的其它步骤,特别是复制过程,并不依赖于HBV并且本身就造成疾病的严重程度和快速演变为肝硬化和HCC。此外,在典型的HDV重叠感染过程中,HBV感染的标志物通常受到抑制,抗HBc抗体IgM和HBVDNA可检测为阴性(Romeo R,Perbellini R.World J Hepatol 2015;7:2389–95;Schaper M等,J Hepatol.2010;52:658–64)。然而,在HDV感染的急性期期间,HBV复制通常被抑制到低水平。在慢性丁型肝炎成立的情况下,这种抑制会持续。
HDV和HBV的合并感染是一种复杂的情况,混合了每种病毒特有的特征和这两种病毒共有的特征。重要的是,最近的研究报道,在用PEG-IFN-2a的HDV标准护理上添加对HBV治疗的标准护理,即通过核苷酸类似物抑制HBV特异性聚合酶,在治疗结束时并未改善HDV应答率(Wedemeyer H等,Lancet Infect.Dis.2019;19:275–286;Mentha N等,J.Adv.Res.2019;17:3–17)。这些发现明确强调了针对HDV复制步骤的替代治疗选择是丁型肝炎所需要的。事实上,洛那法尼(lonafarnib)是一种法尼基转移酶——病毒体组装的必备步骤——的抑制剂,它与HBV无关地抑制HDV复制(申请US20110129549A1;Mentha N,Clnts.google.com/patAlfaiate D.J.Adv.Res.2019;17:3–17)。然而,其毒性阻碍了其在抗HDV疗法中的广泛应用。其它几种针对HDV与HBV HBsAg相互作用的抗病毒分子目前正在开发中:Myrcludex B,它通过抑制HBsAg与NTCP结合来阻止HDV进入肝细胞;siRNA,其使HBVmRNA、包括HBsAg mRNA沉默;以及REP 2139,它被认为抑制肝细胞释放HBsAg并与丁型肝炎抗原相互作用(Ye X等,ACS Infect.Dis.2019;5:738–5:7;Mentha N等,J.Adv.Res.2019;17:3–17)。
因此,抗HDV治疗应抑制至少一个HDV复制步骤。所述复制步骤可以是HDV特异性的,如HDAg-L的异戊二烯化,或通过抑制HBsAg合成、释放或功能而与HBV共享的。理想地,丁型肝炎的治疗通过抑制每种病毒的特异性复制步骤,不仅应抑制HDV复制,还应抑制HBV复制。除了针对这两种病毒共同的HBsAg依赖性的化合物外,尚未报道过可以特异性地抑制HDV复制和HBV复制两者的这类分子。抑制这两种病毒的分子是积极研究的主题,因为当仅针对一种病毒治疗时,难以预测第二种病毒将会如何反应。当抑制一种病毒时,存在另一种病毒被激活或重新激活的风险。例如,在开发抗HCV的抗病毒剂中已经观察到,在合并感染HBV的患者中,当针对HCV时,发生HBV的重新激活(Ma等,Gastroenterology,2018,154,795–798)。因此,合并感染HBV和HDV的患者通常被排除在临床试验之外。事实上,2016年的一篇综述报道,临床试验中纳入的合并感染HDV的患者不到1000名(Guglielmi S等,2016,Revuemédicale Suisse,12,1415-1418)。
发明内容
发明人在HDV单一感染模型中鉴定了几种FXR激动剂能够阻止HDV RNA基因组复制。该结果特别令人惊讶,因为如果FXR激动剂是已知的HBV cccDNA形成和转录抑制剂的话(Mouzannar K等,FASEB J.2018;33:2472–33:2),那么对HDV的效应与HBV的存在无关。因此,FXR激动剂对HDV的作用机制是新的和独创的,作用于特异性HDV复制步骤。此外,本发明人证明了几种FXR激动剂能够抑制两种HDV蛋白、即短丁型肝炎抗原(HDAg-S)和长丁型肝炎抗原(HDAg-L)的生产。在HBV和HDV合并感染模型中,本发明人表明FXR激动剂既抑制病毒的复制又抑制病毒的生产。因此,这些发现开辟了一条用特异性且独立地抑制HDV和HBV复制的新的抗病毒分子类别来治疗丁型肝炎感染、特别是慢性丁型肝炎感染的新途径。
本发明涉及一种法尼醇X受体(farnesoid X receptor,FXR)激动剂,其用于治疗有需要的对象的丁型肝炎病毒(HDV)感染。
任选地,所述对象患有慢性HDV感染。
任选地,所述FXR激动剂是选择性FXR激动剂。
在一个特定的方面,所述FXR激动剂选自LJN452(Tropifexor)、LMB763(Nidufexor)、GS-9674(Cilofexor)、PX-102(PX-20606)、PX-104(Phenex 104)、OCA(Ocaliva)、EDP-305、TERN-101(LY2562175)、MET-409、GW4064、WAY362450(妥芬异丙酯)、Fexaramine、AGN242266(AKN-083)、BAR502和EYP001。
在一个非常特定的方面,所述FXR激动剂是EYP001。
任选地,所述FXR激动剂用于与干扰素α(IFN-α)、干扰素λ或其聚乙二醇化形式、优选选自IFN-α1a、IFN-α1b、IFN-α2a、IFN-α2b和IFN-λ1a或其聚乙二醇化形式、更优选PEG-IFN-α2a(例如Pegasys)、PEG-IFN-α2b(例如ViraferonPeg或Introna)或PEG-IFN-λ1a联合使用。
任选地,所述FXR激动剂用于与抗HDV剂、优选核苷类似物或法尼基转移酶抑制剂联合使用。在一个特定的方面,所述抗HDV剂选自利巴韦林(ribavirin)、利托那韦(ritonavir)、洛那法尼(lonafarnib)和EBP 921。
任选地,所述FXR激动剂用于与抗HBV剂、优选核苷类似物联合使用。在一个特定的方面,所述核苷类似物选自拉米夫定(lamivudine)、阿德福韦(adefovir)、替比夫定(telbivudine)、恩替卡韦(entecavir)、泰诺福韦(tenofovir)和恩曲他滨(emtricitabine)。
任选地,所述FXR激动剂用于与抗HBV/HDV剂、优选核苷类似物、核酸聚合物或NTCP抑制剂联合使用。在一个特定的方面,所述抗HBV/HDV剂选自依折麦布(ezetimibe)、myrcludex B、核酸聚合物REP 2139和核酸聚合物REP 2165。
任选地,所述对象对先前的HDV感染治疗没有反应。在第一个方面,先前的治疗是用PEG-IFNα治疗。在另一个特定方面,先前的治疗是用抗HDV剂治疗。
具体实施方式
本发明涉及一种法尼醇X受体(FXR)激动剂,其用于治疗有需要的对象的丁型肝炎病毒(HDV)感染。
本发明涉及一种治疗有需要的对象的丁型肝炎病毒(HDV)感染的方法,所述方法包括给所述对象施用治疗有效量的法尼醇X受体(FXR)激动剂。
本发明涉及FXR激动剂在制造用于治疗丁型肝炎病毒(HDV)的药物中的用途。
本发明涉及一种包含FXR激动剂的药物组合物,其用于治疗有需要的对象的丁型肝炎病毒(HDV)感染。
患者
如本文所用的“丁型肝炎病毒感染患者”是指感染任何乙型肝炎病毒基因型、例如基因型1、2、3、4、5、6、7、8的患者。
根据本发明,术语“对象”或“患者”和“有需要的对象”或“有需要的患者”意指感染或可能感染丁型肝炎病毒的人类或非人类哺乳动物。在本发明的一些方面,所述对象患有慢性HDV感染。
术语“合并感染患者”是指同时感染HBV和HDV的个体。术语“重叠感染患者”是指先感染HBV、然后感染HDV的个体。
根据本发明的一个方面,术语“治疗失败患者”是指先前的HDV感染治疗失败的个体。因此,本文所用的“治疗失败患者”一般是指对治疗没有反应的HDV感染患者(称为“无反应者”)或起初对治疗有反应但治疗反应没有维持的HDV感染患者(称为“复发者”)。
更具体地说,虽然没有针对HDV的有效治疗、或任何FDA批准的用于治疗慢性HDV的药物,但聚乙二醇化免疫系统调节剂干扰素α(PEG-IFN-α)目前用于临床实践,因此被认为是HDV感染的标准护理。因此,本文所用的“治疗失败患者”一般是指对PEG-IFN-α治疗没有反应的HDV感染患者(称为“无反应者”)或起初对PEG-IFN-α治疗有反应但治疗反应没有维持的HDV感染患者(称为“复发者”)。
治疗
本文所用的术语“治疗”指预防性或防止性治疗以及治愈性或疾病改善性治疗两者,包括对有染病风险或疑似已染病的患者以及生病或已被诊断为患有疾病或医学状况的患者的治疗,包括抑制临床复发。所述治疗可施用于患有医学病症或最终可能获得该病症的对象,以对病症或复发病症的一种或多种症状进行预防、治愈、延迟发作、降低严重性、或加以改善,或为了将对象的存活时间延长到超过没有这样的治疗时的预期存活时间。
疗效可以使用标准方案监测。事实上,治疗后可确定血清中的HDV水平(病毒载量)并测量血清丙氨酸氨基转移酶(ALT)水平。例如,可评估患者血清中是否存在HDV RNA。HDVRNA(IU/mL)可以在治疗期间定期测量,例如,在第1天(给药前以及给药后4、8和12小时)以及在第2天、第3天、第8天、第15天、第29天给药前,以及在第12周、第24周、第36周、第48周、第72周(适用时)给药前,以及在随访时。因此,疗效可以使用国际认可的参数进行监测:a)使用灵敏的基于定量RT-PCR的测定法来监测血清HDV RNA水平,以评估对病毒复制的效果。b)监测血清ALT和/或天冬氨酸氨基转移酶(AST)水平以评估对肝脏炎症和肝细胞死亡的影响。
治疗可对应于仅施用一种FXR激动剂的单药治疗,或对应于与另一种治疗剂例如另一种FXR激动剂或抗病毒剂的联合治疗。
所述治疗可以施用于已诊断为HDV感染的个体。任何上述治疗方案均可以施用于既往HDV感染治疗失败的个体(治疗失败患者)。
FXR激动剂
术语“FXR”是指法尼醇X受体,它是一种由超生理水平的法尼醇激活的核受体(Forman等,Cell,1995,81,687-693)。FXR,又称NR1H4、类视黄醇X受体相互作用蛋白14(RIP14)和胆汁酸受体(BAR)。FXR含有保守的DNA结合结构域(DBD)和C端配体结合结构域(LBD),与多种天然存在的胆汁酸(BA)、包括初级胆汁酸鹅去氧胆酸(CDCA)及其牛磺酸和甘氨酸缀合物结合并被其激活。激活后,所述FXR-RXR异二聚体结合靶基因的启动子区域,并调节参与胆汁酸稳态的几个基因的表达。肝FXR靶基因分为两大类。第一类通过增加输出和减少合成起到降低肝胆汁酸浓度的作用。第二类FXR靶基因,例如磷脂转运蛋白PLTP和载脂蛋白,调节血清中的脂蛋白水平并降低血浆甘油三酯浓度。有关FXR调节基因的更详细列表参见例如WO 03/016288,22-23页。美国专利6,005,086公开了编码哺乳动物FXR蛋白的核酸序列。FXR的人类多肽序列保藏在核苷酸和蛋白质数据库中,登录号为NM_005123、Q96RI1、NP_005114AAM53551、AAM53550、AAK60271。
在本说明书中,术语“FXR激动剂”具有其在本领域中的一般含义,特别是指通过靶向和结合法尼醇X受体(FXR)来发挥作用并且在Maloney等描述的测定法(J.Med.Chem.2000,43:2971-2974)中以至少高于背景的40%激活FXR的化合物。
在一些实施方式中,本发明的FXR激动剂是选择性FXR激动剂。如本文所用的术语“选择性FXR激动剂”是指对一种或多种、理想情况下基本上所有的LXRα、LXRβ、PPARα、PPARγ、PPARδ、RXRα、RARγ、VDR、PXR、ERα、ERβ、GR、AR、MR和PR核受体未表现出显著交叉反应性的FXR激动剂。J.Med.Chem.2009,52,904-907中描述了确定显著交叉反应性的方法。
FXR激动剂是技术人员公知的。
例如,技术人员可从以下出版物(其公开内容通过引用并入本文)中容易地鉴定FXR激动剂:
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通常,FXR激动剂包括类固醇FXR激动剂和非类固醇FXR激动剂的类别。
在本发明的某些实施方式中,所述FXR激动剂选自已在以下公布中公开的充当FXR调节剂的小分子化合物:EP1392714;EP1568706;JP2005281155;US20030203939;US2005080064;US2006128764;US20070015796;US20080038435;US20100184809;US20110105475;US6,984,560;WO2000037077;WO200040965;WO200076523;WO2003015771;WO2003015777;WO2003016280;WO2003016288;WO2003030612;WO2003016288;WO2003080803;WO2003090745;WO2004007521;WO2004048349;WO2004046162;WO2004048349;WO2005082925;WO2005092328;WO2005097097;WO2007076260;WO2007092751;WO2007140174;WO2007140183;WO2008002573;WO2008025539;WO2008025540;WO200802573;WO2008051942;WO2008073825;WO2008157270;WO2009005998;WO2009012125;WO2009027264;WO2009080555;WO2009127321;WO2009149795;WO2010028981;WO2010034649;WO2010034657;WO2017218330;WO2017218379;WO2017201155;WO2017201152;WO2017201150;WO2017189652;WO2017189651;WO2017189663;WO2017147137;WO2017147159;WO2017147174;WO2017145031;WO2017145040;WO2017145041;WO2017133521;WO2017129125;WO2017128896;WO2017118294;WO2017049172;WO2017049176;WO2017049173;WO2017049177;WO2016173397;WO2016173493;WO2016168553;WO2016161003;WO2016149111;WO2016131414;WO2016130809;WO2016097933;WO2016096115;WO2016096116;WO2016086115;WO2016073767;WO2015138986;WO2018152171;WO2018170165,WO2018170166,WO2018170173,WO2018170182,WO2018170167;WO2017078928;WO2014184271;WO2013007387;WO2012087519;WO2011020615;WO2010069604;WO2013037482;US2017275256;WO2005080064;WO2018190643;WO2018215070;WO2018215610;WO2018214959;WO2018081285;WO2018067704;WO2019007418;WO2018059314;WO2017218337;WO2020231917;WO2020211872;WO2020168143;WO2020168148;WO2020156241;WO2020150136;WO2020114307;WO2020061118;WO2020061114;WO2020061112;WO2020061113;WO2020061116,WO2020061117;WO2020011146;WO2020001304;WO2019160813;WO2019120088;WO2019118571;WO2019089667;WO2019089672;WO2019089665;WO2019089664;WO2019089670;其公开内容通过引用并入本文。
在一个方面,所述FXR激动剂可以是以下专利申请中公开的任何FXR激动剂:WO2017/049172,WO2017/049176,WO2017/049173,WO2017/049177,WO2018/170165,WO2018/170166,WO2018/170173,WO2018/170182,和WO2018/170167。
FXR激动剂的具体实例包括但不限于:EYP001,GW4064(如PCT公布号WO 00/37077或US2007/0015796中公开的),6-乙基鹅去氧胆酸,尤其是3α,7α-二羟基7α-二羟基-6α-乙基-5β-胆-24-烷酸,也被称为INT-747;INT-777;6-乙基熊去氧胆酸,INT-1103,UPF-987,WAY-362450,MFA-1,GW9662,T0901317,fexaramine,3β-叠氮基-6α-乙基-7α-羟基-5β-胆-24-烷酸,Tropifexor(LJN452),fexaramine-3(Fex-3),BAR502,BAR704,PX20606,PX20350,3α,7α,11β-三羟基-6α-乙基-5β-胆-24-烷酸(TC-100),6-(4-{[5-环丙基-3-(2,6-二氯苯基)异唑-4-基]甲氧基}哌啶-1-基)-1-甲基-1H-吲哚-3-甲酸,3,6-二甲基-1-(2-甲基苯基)-4-(4-苯氧基苯基)-4,8-二氢-1H-吡唑并[3,4-e][1,4]硫氮杂-7-酮;奥贝胆酸,胆酸,去氧胆酸,甘氨胆酸,甘氨去氧胆酸,牛磺胆酸,牛磺二氢夫地西酸盐,牛磺去氧胆酸,胆酸盐,甘氨胆酸盐,去氧胆酸盐,牛磺胆酸盐,牛磺去氧胆酸盐,鹅去氧胆酸,熊去氧胆酸,牛磺熊去氧胆酸,甘氨熊去氧胆酸,7-B-甲基胆酸,甲基石胆酸,GSK-8062(CAS编号943549-47-1)。在一些实施方式中,所述FXR激动剂选自天然胆汁酸,优选鹅去氧胆酸[CDCA]或牛磺酸-或甘氨酸-缀合的CDCA[牛磺酸-CDCA或甘氨酸-CDCA]以及天然胆汁酸的合成衍生物,优选6-乙基-CDCA或牛磺酸-或甘氨酸-缀合的6-乙基-CDCA,天然非类固醇激动剂,优选二萜类化合物,例如咖啡醇和咖啡豆醇,或合成的非类固醇FXR激动剂。
在一些实施方式中,所述FXR激动剂选自奥贝胆酸(Intercept Pharma),胆酸(CT-RS);GS-9674(Cilofexor)(Phenex Pharmaceuticals AG),Tropifexor(LJN452)(NovartisPharmaceuticals),EYP001,EDP-305,类固醇非羧酸FXR激动剂(EnantaPharmaceuticals),妥芬异丙酯(Pfizer),INT-767(Intercept Pharmaceuticals),LY-2562175(Lilly),AGN-242266(前体为AKN-083,Allergan),EP-024297(EnantaPharmaceuticals),M-480(Metacrine),MET-409(Metacrine),RDX-023(Ardelyx),GW6046,咖啡醇,Fexaramine,以及以CAS编号1192171-69-9标识的化合物PXL007(又名EYP001或EYP001a)(在WO 2009127321中描述)。在一个特定的实施方式中,所述FXR激动剂选自INT-747、以EDP-305标识的化合物、类固醇非羧酸FXR激动剂(Enanta Pharmaceuticals)和以CAS编号1192171-69-9标识的化合物(在WO 2009127321中描述)。
在一个特定的方面,所述FXR激动剂选自LJN452(Tropifexor)、GS-9674(Cilofexor)、LMB763(Nidufexor)、OCA(Ocaliva)、EDP-305、TERN-001和PXL007(又名EYP001)。
在一个特定的方面,所述FXR激动剂选自表1中公开的化合物及其任何药学上可接受的盐。
表1
在本发明的一个优选方面,所述FXR激动剂是EYP001。
可用于本发明中的其它FXR激动剂可以由本领域技术人员基于例如WO 2000/37077中描述的测定法来常规鉴定,WO 2000/37077的教示通过引用整体并入本文。通常,FXR激动剂是使用核受体-肽测定法来鉴定的。该测定法利用荧光共振能量转移(FRET),并且可以用于测试推定的配体是否与FXR结合。所述FRET测定法基于的原理是配体诱导核受体构象变化,从而促进与转录激活所需的辅激活蛋白相互作用。在FRET中,荧光供体分子通过非放射性偶极-偶极相互作用将能量转移给受体分子(通常是荧光分子)。
通常,本发明的FXR激动剂以治疗有效量施用于对象。如上所述的FXR激动剂的“治疗有效量”是指FXR激动剂以适用于任何医学治疗的合理收益/风险比治疗丁型肝炎病毒感染的充分量。然而,应理解的是,本发明的化合物和组合物的总日用量将由主治医师在合理的医学判断范围内决定。任何特定患者的具体治疗有效剂量水平取决于多种因素,包括所治疗的病症和病症的严重程度;所用的具体化合物的活性;所用的具体组成,患者的年龄、体重、一般健康状况、性别和饮食;所用的具体化合物的施用时间、施用途径和排泄速率;治疗持续时间;与所述具体激动剂联合使用的药物;以及医学领域中公知的类似因素。例如,本领域技术人员中众所周知的是化合物的剂量以低于达到期望治疗效果所需的水平开始并逐渐增加剂量直至达到期望的效果。然而,所述产品的日剂量可在每个成人每天0.01至1,000mg的宽范围内变化。优选地,所述组合物含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、250和500mg的所述活性成分,用于对症调整待治疗患者的剂量。药剂通常含有约0.01mg至约500mg的所述活性成分,优选1mg至约100mg的所述活性成分。所述药物的有效量平常以每天0.0002毫克/千克体重至约20毫克/千克体重,特别是每天约0.001毫克/千克体重至7毫克/千克体重的剂量水平供应。
联合疗法
根据本发明的一个方面,本发明的FXR激动剂可与至少一种其它治疗剂联合、优选与至少一种其他抗病毒剂联合、更优选与至少一种选自免疫系统调节剂、抗HDV剂、抗HBV剂、抗HDV/HBV剂的其它抗病毒剂及其任何组合联合施用于所述对象。这些药剂在下文中有更具体的定义。
因此,本发明涉及
-一种FXR激动剂,其与至少一种其它治疗剂联合,用于治疗HDV感染,特别是慢性HDV感染;或
-一种包含FXR激动剂的药物组合物,其与至少一种其它治疗剂联合,用于治疗HDV感染,特别是慢性HDV感染;或
-一种包含FXR激动剂和至少一种其它治疗剂的药物组合物,其用于治疗HDV感染,特别是慢性HDV感染;或
-一种包含FXR激动剂和至少一种其它治疗剂的试剂盒,作为同时、分开或顺序使用的组合制剂,用于治疗HDV感染,特别是慢性HDV感染;或
-一种治疗对象的HDV感染、特别是慢性HDV感染的方法,所述方法包括施用治疗有效量的FXR激动剂和治疗有效量的至少一种其它治疗剂;或
-一种治疗对象的HDV感染、特别是慢性HDV感染的方法,所述方法包括施用包含治疗有效量的FXR激动剂和治疗有效量的至少一种其它治疗剂的药物组合物。
术语“免疫系统调节剂”是指干扰素类型(IFN)的信号传导蛋白,优选干扰素α(IFN-α)或干扰素λ(IFN-λ),更优选聚乙二醇化干扰素α(PEG-IFN-α)或聚乙二醇化干扰素λ(PEG-IFN-λ),更加优选PEG-IFN-α2a、PEG-IFN-α2b或PEG-IFN-λ1a。
在一个方面,IFN选自:复合IFN-α(例如 ),IFN-α1b(例如),IFN-α2a(MOR-22、Inter 2A、Inmutag、Inferon),聚乙二醇化IFN-α2a(例如YPEG-IFNα-2a、Pegaferon),IFN-α2b(例如INTRONAlfarona、Bioferon、Inter 2B、citpheron、Zavinex、Ganapar等等),聚乙二醇化IFN-α2b(例如Albuferon、AOP2014/P1101、Algeron、Pai GeBin),IFN-α2c(例如Berofor Alpha),和干扰素样蛋白(例如Novaferon、HSA-IFN-α2a融合蛋白、HSA-IFN-α2b融合蛋白)。
IFN可以每天一次、每周一次或每周2、3、4、5或6次施用。治疗周期一般较长,例如2周至数月。例如,所述周期从3-4个月直到24个月。剂量可以从1个百万单位到20个百万单位不等,例如2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18或19个百万单位。IFN可以通过皮下、肌内、静脉内、透皮或瘤内施用进行施用,优选皮下或肌内施用。
在一个特定的方面,在治疗开始时,IFN与所述FXR激动剂联合使用。任选地,停止用IFN治疗,而维持用所述FXR激动剂治疗。例如,用FXR激动剂和IFN的第一个治疗周期可持续数天或数周(例如,1、2、3、4、5、6、7、8或9天,或1、2、3、4、5、6、7、8或9周),然后在没有IFN的情况下下用所述FXR激动剂治疗一段时间。该第二步可持续数天、数周或数月。
在一个特定的方面,IFN是IFNα2a、IFNα2b或其聚乙二醇化形式并且每周一次皮下施用,例如剂量从1μg至500μg、优选从10μg至500μg、更优选从100μg至250μg不等,例如100、110、120、130、140、150、160、170、180、190或200μg,并且持续时间从2-4个月直至24个月。在一个非常具体的方面,治疗持续12至52周,优选45至52周,例如48周。在一个更具体的方面,所述IFN是IFNα2a或其聚乙二醇化形式。
术语“抗HDV剂”是指治疗HDV感染从而抑制HDV复制、HDV病毒体组装或抑制HDV病毒体进入可感染细胞的任何化合物。一些抗HDV剂是本领域技术人员已知的(参见Deterding等,2019,AIDS Rev.,21,126-134;Gilman等,2019),World J Gastroenterol.,25,4580-4597)。优选地,所述抗HDV剂选自利巴韦林、利托那韦、洛那法尼和EBP 921。
特别地,抑制HDV复制,对应于在受感染细胞中复制的HDV RNA拷贝数减少约10、20、30、40、50、60、70、80、90%或100%。测量拷贝数的技术,尤其是基于聚合酶链反应(PCR)的技术,是本领域技术人员公知的。优选地,抑制HDV复制的抗HDV剂是核苷类似物。
特别地,抑制HDV病毒体组装对应于在受感染细胞中组装的HDV病毒体的量减少约10、20、30、40、50、60、70、80、90或100%。定量病毒体的量的技术,特别是基于酶联免疫吸附测定(ELISA)的技术,是本领域技术人员公知的。优选地,抑制HDV病毒体组装的抗HDV剂是法尼基转移酶抑制剂。
特别地,抑制HDV病毒体进入可感染细胞对应于进入可感染细胞的HDV病毒体的量减少约10、20、30、40、50、60、70、80、90或100%。
术语“抗HBV剂”是指治疗HBV感染从而抑制HBV复制、抑制HBV病毒体组装、或抑制HBV病毒体进入可感染细胞的化合物。抗HBV剂是本领域技术人员已知的,例如常规干扰素、聚乙二醇干扰素、核苷和核苷酸类似物(参见Terrault等,2018)。优选地,所述抑制HBV复制的抗HBV剂是核苷类似物,更优选核苷类似物逆转录酶抑制剂,更加优选地,所述抗HBV剂选自拉米夫定、阿德福韦、替比夫定、恩替卡韦、泰诺福韦和恩曲他滨。
特别地,抑制HBV复制对应于在受感染细胞中HBV DNA复制的量减少约10、20、30、40、50、60、70、80、90%或100%。
HBV DNA复制水平下降有助于降低HBV病毒体组装水平,这进而诱导了其它靶细胞的感染水平下降。因此,出现了为HDV病毒体组装提供HBV抗原的概率下降。
特别地,抑制HBV病毒体组装对应于在受感染细胞中组装的HBV病毒体的量减少约10、20、30、40、50、60、70、80、90或100%。
HBV病毒体的HBV病毒体组装水平下降诱导了其它靶细胞感染水平下降,因此为HDV病毒体组装提供HBV抗原的概率下降。
特别地,抑制HBV病毒体进入可感染细胞对应于进入可感染细胞中的HBV病毒体的量减少约10、20、30、40、50、60、70、80、90或100%。
术语“可感染细胞”是指病毒体可接近的细胞,这些细胞表达HDV病毒体或HBV病毒体进入该细胞所需的NTCP受体。细胞,特别是宿主细胞,当没有生物或物理屏障防止其与循环病毒体接触时,被认为是可接近的。
由于HBV和HDV病毒体共享相同的进入受体,即NTCP,因此抗HBV剂对NTCP的对接介导的阻断有效抑制HBV病毒体的细胞进入,也抑制HDV病毒体的细胞进入。
术语“抗HBV/HDV剂”是指治疗HDV和/或HBV感染从而抑制HBV和HDV病毒体组装、或抑制HBV和HDV病毒体进入可感染细胞中的化合物。优选地,所述抗HBV剂选自依折麦布、myrcludex B、核酸聚合物REP 2139和核酸聚合物REP 2165或其任何组合。
特别地,抑制HBV和HDV病毒体组装分别对应于在受感染细胞中组装的HBV病毒体或HDV病毒体的量减少约10、20、30、40、50、60、70、80、90或100%。优选地,抑制HBV或HDV病毒体组装的抗HBV/HDV剂是核酸聚合物,更优选阻断HBAg分泌的核酸聚合物。
特别地,抑制HBV病毒体和HDV病毒体进入可感染细胞对应于进入可感染细胞中的HBV病毒体和HDV病毒体的量减少约10、20、30、40、50、60、70、80、90或100%。优选地,抑制HBV或HDV进入可感染细胞的抗HBV/HDV剂是NTCP抑制剂,更优选NTCP-对接抑制剂。
根据本发明的一个优选方面,本发明的FXR激动剂可与至少一种选自如上定义的免疫系统调节剂、抗HDV剂、抗HBV剂、抗HDV/HBV剂的其它抗病毒剂及其任何组合联合施用于所述对象。优选所述其它抗病毒剂选自干扰素类型的免疫系统调节剂、核苷类似物、核苷酸类似物、核酸聚合物、法尼基转移酶抑制剂、蛋白酶抑制剂、NTCP抑制剂及其任何组合。
更优选地,本发明的FXR激动剂可与PEG-IFN-α2a、PEG-IFN-α2b或PEG-IFN-λ1a、利巴韦林、利托那韦、洛那法尼和EBP 921、拉米夫定、阿德福韦、替比夫定、恩替卡韦、泰诺福韦和恩曲他滨、依折麦布、myrcludex B、核酸聚合物REP 2139和核酸聚合物REP 2165及其任何组合联合,施用于所述对象。
根据一个具体方面,本发明的FXR激动剂可与PEG-IFN-α2a联合施用于所述对象。
或者,本发明的FXR激动剂可与myrcludex B联合施用于所述对象。
或者,本发明的FXR激动剂可与利托那韦联合施用于所述对象。
或者,本发明的FXR激动剂可与洛那法尼联合施用于所述对象。
或者,本发明的FXR激动剂可与阿德福韦联合施用于所述对象。
或者,本发明的FXR激动剂可与PEG-IFN-α2a和另一种药剂、优选与PEG-IFN-α2a和myrcludex B联合施用于所述对象。
或者,本发明的FXR激动剂可与PEG-IFN-α2a和利托那韦联合施用于所述对象。
或者,本发明的FXR激动剂可与PEG-IFN-α2a和洛那法尼联合施用于所述对象。
或者,本发明的FXR激动剂可与PEG-IFN-α2a和阿德福韦联合施用于所述对象。
在本发明的一个方面,所述联合疗法的施用是同时的,使得所述FXR激动剂和至少一种其它药剂同时施用于所述对象。
在本发明的另一个方面,所述联合疗法的施用是顺序的,使得所述FXR激动剂和至少一种其它药剂以确定的时间延迟,优选约1至10天、更优选约1至24小时、更加优选约1至12小时,顺序施用于所述对象。
在一个具体方面,所述FXR激动剂不与干扰素联合使用。
本发明将通过以下附图和实施例进一步说明。然而,这些实施例和附图不应以任何方式解释为限制本发明的范围。
附图:
图1.FXRα激动剂抑制HBV-HDV合并感染的dHepaRG细胞中的HDV复制。用HBV以100GE/细胞的MOI并用HDV以10GE/细胞的MOI感染分化的HepaRG细胞。从感染后第3天到第13天,用10μM GW4064、干扰素α-2a(1000IU/mL)或介质处理细胞。在第13天收获细胞和上清液用于定量细胞内HBV和HDV RNA以及分泌抗原。结果是以一式三份生物学重复进行的两个实验的平均值+/-SD。
图2.FXRα激动剂抑制重叠感染了HDV的HBV感染dHepaRG中的HDV复制。用HBV以100GE/细胞的MOI并在7天后用HDV以10GE/细胞的MOI感染分化的HepaRG细胞。从HBV感染后第10天到第17天,用1、5或10μM GW4064、干扰素α-2a(1000IU/mL)或介质处理细胞。在第17天收获细胞和上清液用于定量细胞内HDV RNA。结果是以一式三份生物学重复进行的三个实验(在dHepaRG中)的平均值+/-SD。
图3.FXRα激动剂抑制重叠感染了HDV的HBV感染PHH中的HDV复制。用HBV以100GE/细胞的MOI并在4天后用HDV以10GE/细胞的MOI感染PHH。从HBV感染后第7天到第14天,用1、5或10μM GW4064、干扰素α-2a(1000IU/mL)或介质处理细胞。在HBV感染后第14天收获细胞和上清液用于定量细胞内HDV RNA。结果是以一式三份生物学重复进行的一个实验的平均值+/-SD。
图4.FXRα激动剂抑制重叠感染了HDV的HBV感染dHepaRG中HDV蛋白的生产。用HBV以100GE/细胞的MOI并在7天后用HDV以10GE/细胞的MOI感染分化的HepaRG细胞。从HBV感染后第10天到第17天,用1、5或10μM GW4064、干扰素α-2a(1000IU/mL)或介质处理细胞。在HBV感染后第17天收获细胞并裂解用于蛋白质提取和WB分析。图表现了各个印迹的密度测定分析,结果表示为相对于B-微管蛋白水平归一化的HDAg的比率。
图5.FXRα激动剂抑制重叠感染了HDV的HBV感染PHH中HDV蛋白的生产。用HBV以100GE/细胞的MOI并在4天后用HDV以10GE/细胞的MOI感染PHH。从HBV感染后第7天到第14天,用1、5或10μM GW4064、干扰素α-2a(1000IU/mL)或介质处理细胞。在HBV感染后第14天收获细胞和上清液用于定量细胞内HDV RNA并裂解用于蛋白质提取和WB分析。图表现了各个印迹的密度测定分析,结果表示为相对于B-微管蛋白水平归一化的HDAg的比率。
图6.FXRα激动剂抑制单独感染的dHepaRG细胞中的HDV复制。用HDV以25GE/细胞的MOI感染分化的HepaRG细胞。从感染后第4天到第11天,用1或10μM GW4064、10μM 6-ECDCA和1μM tropifexor处理细胞。在HDV感染后第11天,收集细胞并通过qPCR定量总细胞内HDVRNA。
图7.FXRα激动剂降低单独感染的dHepaRG细胞中HDV基因组RNA的量。用HDV以25GE/细胞的MOI感染分化的HepaRG细胞。从感染后第4天到第11天,用1或10μM GW4064、10μM 6-ECDCA和1μM tropifexor处理细胞。在HDV感染后第11天,收集细胞并通过Northern印迹分析HDV基因组RNA。
图8.用FXRα激动剂处理的HBV/HDV合并感染dHepaRG中新生HDV RNA水平的降低。用HBV(100vge/细胞)和HDV(10vge/细胞)合并感染dHepaRG。6天后,将细胞用GW4064(10μM)或用干扰素α-2a(1000U/mL)处理4天。细胞与标记的尿苷或不与标记的尿苷(假EU)一起温育2小时,洗涤并收获。分离和通过RT-qPCR分析定量总细胞内HDV RNA以及EU标记的HDVRNA(新生细胞内HDV RNA)。作为对照,将细胞在与标记的尿苷一起温育之前用放线菌素D(10μg/mL,ActD)处理20分钟,以阻断新生RNA的转录。结果是以一式三份生物学重复进行的一个实验的平均值+/-SD。
图9.GW4064降低HDV粒子的感染性。将dHepaRG细胞用HBV和HDV以500vge/细胞的HBV和50vge/细胞的HDV合并感染。3天后将细胞用或不用GW4064(10μM)、IFN-α(500UI/mL)或拉米夫定(LAM,10μM)处理10天。(A)收集感染dHepaRG细胞的上清液,通过PEG沉淀浓缩,并通过qRT-PCR分析评估细胞外HDV RNA的水平。(B-C)将稚HuH7.5-NTCP细胞用不同浓缩的上清液感染,(B)500vge/细胞,(C)如指示。六天后,通过RT-qPCR分析评估细胞内HDV RNA的水平。RT-qPCR的结果是三个独立实验的平均值+/-SD,每个实验以一式三份生物学重复进行。
实施例
结果
为了确定FXR激动剂对HDV感染的影响,在分化的HepaRG细胞(dHepaRG)和原代人肝细胞(PHH)中进行了体外感染。
分化后,HepaRG细胞易受体外产生的HDV病毒体的感染,无论是单独感染,还是与HBV合并感染和重叠感染。在HBV/HDV合并感染或重叠感染的细胞的情况下,该模型允许研究HDV复制周期的所有步骤,包括穿透到细胞中、病毒基因组易位到细胞核中、病毒基因组复制和病毒mRNA合成,以及病毒周期的后期阶段,即带有HBV HBs包膜蛋白的感染性病毒体的组装和分泌。在HDV单独感染的细胞中,可以研究病毒周期的所有步骤,但组装过程除外,因为缺乏新合成的HBV包膜蛋白。
PHH也易受到体外产生的HDV病毒体的感染,无论是单独感染,还是与HBV的合并感染和重叠感染。
用FXR调节剂处理抑制HBV/HDV合并感染的HepaRG细胞中的HDV复制
本发明人首先评价了FXRα激动剂对体外合并感染的dHepaRG细胞中HDV复制的影响。将细胞同时感染HBV和HDV。感染后三天,用10μM的FXR激动剂GW4064或1000IU/mL的干扰素α-2a处理细胞10天。在感染后第13天,收集细胞和上清液。对细胞内HDV RNA和HBV RNA的量以及分泌的HBe和HBs抗原进行定量。
在HepaRG中,10μM的GW4064使总细胞内HDV RNA的量减少了60%(图1A)。病毒RNA的这种减少与用干扰素α-2a观察到的相当。以前描述过的GW4064的抗HBV活性,在细胞内HBV RNA的量和分泌的HBs和HBe抗原上得到了验证(图1B,1C和1D)。
用FXR调节剂处理抑制HBV和HDV重叠感染的细胞中的HDV复制
还在HBV感染的肝细胞(dHepaRG细胞和PHH二者)的HDV重叠感染体外模型中评价了FXRα激动剂对HDV复制的影响。将细胞连续感染HBV,并在7天后感染HDV。HDV感染后3天,用1、5和10μM的GW4064或1000UI/mL干扰素α-2a处理细胞7天。通过RT-qPCR定量总细胞内HDV RNA的量。
在dHepaRG细胞和PHH二者之中,用FXR激动剂GW4064处理降低了总细胞内HDV RNA的量,在10μM时高达在HepaRG细胞中的60%(图2)和在PHH中的45%(图3)。效果在1μM时已经非常明显。病毒RNA的这种减少与用1000IU/mL的干扰素α-2a观察到的相当。
重要的是,通过Western印迹分析进行检测,用GW4064处理还在重叠感染的dHepaRG细胞(图4)和PHH(图5)中都降低了HDV抗原(HDAg)的量。值得注意的是,FXRα激动剂减少HDAg-L(大HDV抗原)和HDAg-S(小HDV抗原)的比例相同,即在这两种模型中它们的的量均降低了75%。用10μM的GW4064处理后对HDAg的抑制比用1000IU/mL的干扰素α-2a得到的结果略高。总之,这些结果表明FXRα激动剂GW4064很可能在mRNA水平上抑制HDV,从而导致在蛋白质水平上非常强的抑制。
用FXR调节剂处理抑制HDV单独感染的细胞中的HDV复制
为了确定FXRα介导的HDV抑制是否独立于HBV,本发明人在HDV单独感染的dHepaRG细胞中分析了FXRα激动剂的影响。单独用HDV感染后4天,将细胞用3种不同的FXRα激动剂处理7天:10μM的6-ECDCA、1和10μM的GW4064、和1μM的tropifexor。处理对总HDV RNA量的影响通过RT-qPCR进行分析。通过Northern印迹分析来评价FXR激动剂对基因组HDV RNA的量的具体影响。
通过RT-qPCR(图6)测量以及通过Northern印迹检测的基因组RNA(图7),10μM 6-ECDCA、6-ECDCA和tropifexor均将总HDV RNA的量减少约60%。
总之,这些结果表明FXRα激动剂抑制HDV感染的方式与其对HBV感染的抑制效果无关。此外,3种具有不同结构的不同FXRα激动剂在HDV抑制方面表现出相似的效率。
用FXR调节剂处理抑制新生HDV RNA的合成
为了初步了解FWR激动剂对HDV的作用方式,本发明人在HBV/HDV合并感染的dHepaRG细胞中进行了Run-ON测定,以确定新生的HDV RNA是否也可以被抑制,因为总HDVRNA量已表明被抑制。将dHepaRG细胞同时感染HBV和HDV。感染后6天,用10μM GW4064处理细胞4天,然后进行Run-On实验。结果表明,10μM的GW4064确实能够在用标记的尿苷染色的2小时内抑制HDV RNA合成,因此提示可能影响了HDV mRNA的起始和/或延伸(图8)。
用FXR调节剂处理抑制分泌的HDV病毒粒子的特异感染性
在体外合并感染的dHepaRG细胞中评价了FXRα激动剂对HDV病毒粒子的分泌和特异感染性的影响。感染后三天,用10μM的FXR激动剂GW4064或1000IU/mL的干扰素α-2a或10μM的拉米夫定处理细胞10天。收集上清液并使用8%PEG 8000浓缩。首先,通过RT-qPCR来定量HDV RNA的分泌量。结果表明,10μM的GW4064使HDV RNA的分泌减少了65%(图9A)。这种病毒RNA的减少比用干扰素α-2a(50%)观察到的稍微更明显。正如所料,用作对照的HBV聚合酶抑制剂拉米夫定没有显著改变HDV RNA分泌。
然后,为了确定分泌的HDV粒子的特异感染性,使用从dHepaRG上清液中收集的浓缩的HDV病毒粒子感染稚Huh7.5-NTCP细胞,对每种条件使用相同的vge/细胞。感染后6天,通过RT-qPCR对总细胞内HDV RNA进行定量。结果表明,用500vge/细胞感染后,从用FXR激动剂GW4064处理的dHepaRG获得的上清液感染的细胞中,细胞内HDV RNA的量减少了大于95%(图9B),与此相比,在干扰素α-2a条件下减少了70%。用拉米夫定处理未改变HDV粒子的特异感染性。
最后,用相同的浓缩上清液感染稚Huh7.5-NTCP细胞,但对于每种条件,使用两种不同的HDV接种物,100和500vge/细胞。感染后6天对细胞内HDV RNA的定量显示,从用介质、干扰素α-2a或拉米夫定处理的dHepaRG收集的上清液感染的细胞中,HDV RNA水平均呈剂量依赖性增加(图9C)。然而,使用从用FXR激动剂GW4064处理的dHepaRG细胞收集的上清液,情况并非如此,因为当用100或500vge/细胞感染稚Huh7.5-NTCP细胞时没有观察到显著差异。总之,这些结果表明FXR激动剂GW4064重度降低了分泌的HDV粒子的感染性质。
结论
本发明人发现,在体外研究HDV感染的两个最相关模型——dHepaRG和PHH中,FXR激动剂是HDV复制的抑制剂。用三种不同的FXR激动剂,即一种胆汁酸类似物(6-ECDCA)和2种合成激动剂(GW4064和tropifexor),证明了这种抗病毒效果。
在HDV单独感染细胞中进行的实验呈现的结果明确证明,FXR激动剂对HDV复制的抑制效果与先前鉴定的此类分子对HBV的影响无关。尽管HDV依赖HBV表面蛋白进入肝细胞,但病毒周期的复制步骤的发生与HBV无关。正如本发明人观察到的,基因组形式的HDV RNA以及新生RNA的量在处理后均减少,FXR激动剂可能针对HDV生命周期的复制步骤。
此外,本发明人发现FXR激动剂也是dHepaRG细胞中HDV分泌以及分泌的病毒粒子特异感染性的抑制剂。用合成的激动剂GW4064证明了这种抗病毒效果。
总之,本发明人已经鉴定出特异性调节(抑制)HDV感染的新分子(即FXR激动剂)。这应该允许选择可以在动物模型中测试或已在临床试验中用FXR激动剂直接在人体中测试的候选者。
材料&方法
细胞系
HepaRG
源自人肝细胞癌的HepaRG细胞系在限定条件下培养4周后可以分化并恢复肝细胞的许多表型特征1。如前所述2,3,对HepaRG细胞进行培养、分化、以及感染HBV和HDV。简而言之,为了分化,将细胞在标准培养基中维持2周,然后在补充有1.8%DMSO的标准培养基中维持至少2周。标准培养基的组成如下:William E培养基,补充有10%HyCLone FetalCloneII血清(Thermo Fisher Scientific)、青霉素/链霉素、L-谷氨酰胺、胰岛素-转铁蛋白-硒(Gibco)和50μM氢化可的松半琥珀酸盐。
原代人肝细胞
如前所述4,从具有法国部长授权(AC 2013-1871,DC 2013–1870,AFNOR NF 96900,2011年9月)的Centre Léon Bérard(里昂)获得的人肝切除术新鲜制备原代人肝细胞(PHH)。
Huh7.5NTCP
Huh7.5细胞由C.M.Rice(洛克菲勒大学(Rockefeller University),美国)友情提供。如前所述(Ni等.,Gastroenterology,2014;146(4):1070-83.doi:10.1053/j.gastro.2013.12.024.2013年12月19日电子发表.PMID:24361467),通过慢病毒转导产生衍生的Huh7.5NTCP细胞。
病毒
如前所述3,5,从共转染的Huh7细胞的上清液制备HDV储液(stocks)(基因型1,Genbank ID M21012)。用于生产感染性HDV粒子的质粒pSVLD3和pT7HB2.7由CamilleSureau(Laboratoire de virologiemoléculaire,Inserm UMR S_1134,国家输血研究所(Institut National de Transfusion Sanguine),法国巴黎)友情提供。
HBV储液(基因型D,Genbank ID U95551)根据先前描述的方案7,使用HepAD38细胞系制备。
将含有HBV或HDV粒子的上清液澄清(0.45μm过滤器)并用8%PEG 8000(Sigma-Aldrich)浓缩。
化学物质
GW4064[3-(2,6-二氯苯基)-4-(3-羧基-2-氯-芪-4-基)-氧甲基-5-异丙基异唑]是一种FXR激动剂(EC50 90nM),在体内和体外都有活性8。虽然表现出有限的生物利用度,但GW4064作为一种强大并且选择性的FXR激动剂得到了广泛的应用,并已达到该领域中“参比化合物”的地位。
6-ECDCA(6-乙基鹅去氧胆酸)是一种胆汁盐衍生物和强FXR激动剂(EC50 99nM)并得自Sigma-Aldrich9。
Tropifexor(2-[(1R,3r,5S)-3-({5-环丙基-3-[2-(三氟甲氧基)苯基]-1,2-唑-4-基}甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基]-4-氟-1,3-苯并噻唑-6-甲酸)是一种合成FXR激动剂,在体外和体内都有活性,得自Cayman10。
GW4064、6-ECDCA和tropifexor均以10mM溶解于DMSO中,制备储用溶液。
干扰素α-2(ROFERON-A)购自Roche。
放线菌素D购自Sigma-Aldrich。
拉米夫定(LAM)购自Selleckchem。
Western印迹
在含有蛋白酶抑制剂(来自Sigma-Aldrich的蛋白抑制剂混合物(ProteinCocktail Inhibitors),NaF 10mM,原钒酸钠10mM)的RIPA裂解缓冲液(NaCl 150mM,TrisHCl pH=8,0 50mM,SDS 0,1%,NP401%,去氧胆酸钠0,5%)中收获细胞。根据制造商(Biorad),使用TransTurbo Blot仪器对澄清的裂解物进行10%SDS-PAGE并将Western印迹转移到PVDF或硝酸纤维素膜上。一级抗体是HDVAg抗体(Alain Kay博士的友好馈赠)和β-微管蛋白抗体(Abcam)。二级HRP抗体购自Sigma-Aldrich。HRP信号检测是使用Ozyme–SyngenePXi图像系统和严格设置在饱和点以下的参数以电子方式确定的。
Northern印迹
使用Tri(TR118,分子研究中心(Molecular Research Center))从感染细胞中提取总RNA。对于每个样本,将2μg总RNA在1.2%琼脂糖凝胶中进行电泳。电转移到带电尼龙膜(Roche)后,使用通过使用Dig RNA标记试剂盒(Sp6/T7)(Roche)和DIG发光检测试剂盒(Roche)根据制造商的说明合成的链特异性RNA探针来检测基因组HDV RNA序列。用ImageLab进行信号的定量。
作为提取的RNA的量和质量的内部对照,对所述膜进行剥离并使用标记的人18SrRNA和28S rRNA特异性寡核苷酸再杂交。
HBs和HBe定量
在按要求稀释后,在Mini Vidas仪器上用Vidas HBs和Vidas HBE/HBET试剂盒(bioMérieux,法国)或Autobio试剂盒(AutoBio,中国),根据制造商的方案定量在细胞上清液中分泌的HBs和HBe抗原。
通过qPCR定量病毒RNA
使用NucleoSpin RNA Plus(Macherey-Nagel)制备总RNA。用TURBO DNase(Ambion)消化DNA后,使用High-Capacity RNA-to-cDNA试剂盒(Thermo FisherScientific)逆转录最多1000ng RNA。用引物HDV-F(5’-GCCTCTCCTTGTCGGTGAAT-3’,SEQ IDNO:1)和HDV-R(5’-CCTGGCTGGGGAACATCAAA-3’,SEQ ID NO:2)进行定量PCR来定量总HDVRNA以及HBV-F(5’-AGCTACTGTGGAGTTACTCTCGT-3’,SEQ ID NO:3)和HBV-R(5’-CAAAGAATTGCTTGCCTGAGTG-3’,SEQ ID NO:4)来定量前基因组/前核心HBV RNA。使用QuantiFastGreen PCR试剂盒(Qiagen),在480仪器(Roche)上通过定量PCR(qPCR)使用45个PCR循环来分析cDNA。所有测定一式三份进行。将每个基因的表达相对于使用引物S9-F(5’-CCGCGTGAAGAGGAAGAATG-3’,SEQ ID NO:5)和S9-R(5’-TTGGCAGGAAAACGAGACAAT-3’,SEQ ID NO:6)的S9管家基因进行归一化,来确定相对定量。
Run-On测定
HDV感染的HepaRG细胞与标记的尿苷或不与标记的尿苷(假EU)一起温育2小时,洗涤并收获。使用Click-iTTM新生RNA捕获试剂盒(Click-iTTMNascent RNA Capture Kit)(Thermofisher Scientific),根据制造商的说明分离总细胞内HDV RNA以及EU标记的HDVRNA(新生细胞内HDV RNA)。作为对照,将细胞在与标记的尿苷一起温育之前用10μg/mL的放线菌素D处理20分钟,以阻断新生RNA的转录。
HDV分泌和特异感染性分析
为了分析HDV病毒体的特异感染性,使用8%PEG 8000浓缩来自用HBV和HDV二者感染的dHepaRG的上清液。通过RT-qPCR定量浓缩液中的HDV RNA,并对每种处理条件均使用相同病毒基因组当量(vge)的浓缩病毒来感染Huh7.5NTCP细胞。感染后6天,提取总细胞RNA并通过RT-qPCR定量HDV RNA。
参考书目
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序列表
<110> 法国国家卫生及研究医学协会(INSERM)
里昂高等师范学院(ECOLE NORMALE SUPERIEURE DE LYON)
克洛德贝纳尔-里昂第一大学(UNIVERSITE CLAUDE BERNARD LYON 1)
法国国家科学研究中心(CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE)
埃尼奥制药公司(ENYO PHARMA)
<120> FXR激动剂在治疗丁型肝炎感染中的用途
<130> SCT222772-20
<141> 2021-01-14
<150> 20305024.0 EP
<151> 2020-01-15
<160> 6
<170> SIPOSequenceListing 1.0
<210> 1
<211> 20
<212> DNA
<213> 人工序列
<220>
<221> misc_feature
<222> (1)..(20)
<223> 引物HDV-F
<400> 1
gcctctcctt gtcggtgaat 20
<210> 2
<211> 20
<212> DNA
<213> 人工序列
<220>
<221> misc_feature
<222> (1)..(20)
<223> 引物HDV-R
<400> 2
cctggctggg gaacatcaaa 20
<210> 3
<211> 23
<212> DNA
<213> 人工序列
<220>
<221> misc_feature
<222> (1)..(23)
<223> 引物HBV-F
<400> 3
agctactgtg gagttactct cgt 23
<210> 4
<211> 22
<212> DNA
<213> 人工序列
<220>
<221> misc_feature
<222> (1)..(22)
<223> 引物HBV-R
<400> 4
caaagaattg cttgcctgag tg 22
<210> 5
<211> 20
<212> DNA
<213> 人工序列
<220>
<221> misc_feature
<222> (1)..(20)
<223> 引物S9-F
<400> 5
ccgcgtgaag aggaagaatg 20
<210> 6
<211> 21
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<213> 人工序列
<220>
<221> misc_feature
<222> (1)..(21)
<223> 引物S9-R
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ttggcaggaa aacgagacaa t 21
Claims (15)
1.一种法尼醇X受体(FXR)激动剂,其用于治疗有需要的对象的丁型肝炎病毒(HDV)感染。
2.根据权利要求1所述的用途的FXR激动剂,其中所述对象患有慢性HDV感染。
3.根据权利要求1或2所述的用途的FXR激动剂,其中所述FXR激动剂是选择性FXR激动剂。
4.根据权利要求1至3中任一项所述的用途的FXR激动剂,其中所述FXR激动剂选自LJN452(Tropifexor)、LMB763(Nidufexor)、GS-9674(Cilofexor)、PX-102(PX-20606)、PX-104(Phenex 104)、OCA(Ocaliva)、EDP-305、TERN-101(LY2562175)、MET-409、GW4064、WAY362450(妥芬异丙酯)、Fexaramine、AGN242266(AKN-083)、BAR502和EYP001。
5.根据权利要求1至3中任一项所述的用途的FXR激动剂,其中所述FXR激动剂是EYP001。
6.根据权利要求1至5中任一项所述的用途的FXR激动剂,其用于与干扰素α(IFN-α)、干扰素λ或其聚乙二醇化形式、优选选自IFN-α1a、IFN-α1b、IFN-α2a、IFN-α2b和IFN-λ1a或其聚乙二醇化形式、更优选PEG-IFN-α2a(例如Pegasys)、PEG-IFN-α2b(例如ViraferonPeg或Introna)或PEG-IFN-λ1a联合使用。
7.根据权利要求1至6中任一项所述的用途的FXR激动剂,其用于与抗HDV剂、优选核苷类似物或法尼基转移酶抑制剂联合使用。
8.根据权利要求7所述的用途的FXR激动剂,其中所述抗HDV剂选自利巴韦林、利托那韦、洛那法尼和EBP 921。
9.根据权利要求1至8中任一项所述的用途的FXR激动剂,其用于与抗HBV剂、优选核苷类似物联合使用。
10.根据权利要求9所述的用途的FXR激动剂,其中所述核苷类似物选自拉米夫定、阿德福韦、替比夫定、恩替卡韦、泰诺福韦和恩曲他滨。
11.根据权利要求1至8中任一项所述的用途的FXR激动剂,其用于与抗HBV/HDV剂、优选核苷类似物、核酸聚合物或NTCP抑制剂联合使用。
12.根据权利要求11所述的用途的FXR激动剂,其中所述抗HBV/HDV剂选自依折麦布、myrcludex B、核酸聚合物REP 2139和核酸聚合物REP 2165。
13.根据权利要求1至9中任一项所述的用途的FXR激动剂,其中所述对象对先前的HDV感染治疗没有反应。
14.根据权利要求13所述的用途的FXR激动剂,其中先前的治疗是用PEG-IFNα治疗。
15.根据权利要求13所述的用途的FXR激动剂,其中先前的治疗是用抗HDV剂治疗。
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