CN110944635A - 用于减少附加体病毒的持久性和表达的方法和药物组合物 - Google Patents
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Abstract
发明人意外发现，在来自不像肝脏或肠道一样专门用于胆汁盐合成和运输的组织的细胞中，FXR在维持活性病毒附加体方面起决定性作用。特别地，本发明人表明，FXR激动剂可适用于抑制以附加体和染色体外形式的DNA存在于细胞中的病毒(例如BKV和HIV‑1)的复制。因此，本发明涉及减少有需要的受试者中附加体病毒的持久性和表达的方法，包括向受试者施用治疗有效量的FXR激动剂。
Description
技术领域
本发明涉及用于减少有需要的受试者的附加体病毒的持久性和减少的方法和药物组合物。
背景技术
众多DNA病毒的复制中间体在其生命周期中被组织成核染色质样结构，通常称为附加体。例如并且通常，乳多空病毒、猿猴病毒40(SV40)和多瘤病毒的环状基因组以由在核小体中组织的细胞组蛋白组成的微染色体的形式存在。其他病毒，例如α疱疹病毒，例如单纯疱疹病毒1型，和γ疱疹病毒，例如Epstein-Barr病毒和Kaposi肉瘤相关的疱疹病毒的潜伏性基因组维持附加体核染色质的形式。之前的研究发现，经历高活性的抗逆转录病毒治疗(HAART)的患者表现出未整合的附加体HIV-1DNA的水平升高，提示新发感染(Buzón MJ,Massanella M,Llibre JM,等.HIV-1replication and immune dynamics are affectedby raltegravir intensification of HAART-suppressed subjects.Nat.Med.2010；16(4):460–465)。还显示某些组织，例如淋巴结和肠相关的淋巴组织，具有升高的附加体病毒DNA水平，表明这些组织是重新复制的潜在位点。因此，对于根除附加体病毒的持久性的方法和药物组合物存在未满足的需求。
最近的研究表明，FXR激动剂可能适用于治疗乙肝病毒(HBV)感染(WO2015036442)，并表明HBV复制和改变的肝脏胆汁盐代谢稳态和FXR调节似乎是相互依赖的，这可能有助于HBV感染的持久性。然而，尚未研究FXR在附加体病毒的持久性中的作用。
发明简述
本发明涉及用于减少有需要的受试者的附加体病毒的持久性和表达的方法和药物组合物。尤其是，本发明通过权利要求限定。
发明详述
发明人意外发现，在来自不像肝脏或肠道一样专门用于胆汁盐合成和运输的组织的细胞中，FXR在维持活性病毒附加体方面起决定性作用。特别地，本发明人表明，FXR激动剂可适用于抑制以附加体和染色体外形式的DNA存在于细胞中的病毒(例如BKV和HIV-1)的复制。
因此，本发明的第一个目的涉及减少有需要的受试者中附加体病毒的持久性和表达的方法，包括向受试者施用治疗有效量的FXR激动剂。
在一些实施方案中，受试者可以是易感染附加体病毒的人或任何其他动物(例如，鸟类和哺乳动物)(例如家畜，例如猫和狗；牲畜和农场动物，例如马、牛、猪、鸡等)。通常，所述受试者是哺乳动物，包括非灵长类动物(例如，骆驼、驴、斑马、牛、猪、马、山羊、绵羊、猫、狗、大鼠和小鼠)和灵长类动物(例如，猴子、黑猩猩和人)。在一些实施方案中，受试者是非人动物。在一些实施方案中，受试者是农场动物或宠物。在一些实施方案中，受试者是人。在一些实施方案中，受试者是人类婴儿。在一些实施方案中，受试者是人类儿童。在一些实施方案中，受试者是成年人。在一些实施方案中，受试者是老年人。在一些实施方案中，受试者是人类早产儿。
如本文所用，术语“附加体病毒”是指需要附加体复制以在受试者中持续存在的病毒。附加体复制意味着病毒能够复制而不整合到宿主的染色体DNA中，并且不会从分裂的宿主细胞中逐渐损失，这也意味着所述病毒以游离方式复制。通过扩展，“附加体病毒”也指至少在其基因组复制和转录的某些步骤中需要存在核染色体外形式的DNA进行复制的病毒。例如，对于逆转录病毒，在感染后，线性双链逆转录病毒DNA(dsDNA)一旦进入宿主细胞就通过逆转录产生。然后逆转录病毒dsDNA作为染色体外DNA被易位到细胞核中，这是一种强制性的复制中间体。在那里，病毒dsDNA可以整合到细胞核染色质中或环化以形成单或双LTR附加体。逆转录病毒携带ori且宿主细胞提供小DNA病毒的同源复制蛋白，其用于环状DNA逆转录病毒基因组的扩增和复制。
感染脊椎动物的附加体病毒的实例包括但不限于属于腺病毒科(Adenoviridae)、逆转录病毒科(Retroviridae)、疱疹病毒科(Herpesviridae)、乳多空病毒科(多瘤病毒科(Polyomaviridae)和乳头瘤病毒科(Papillomaviridae))、细小病毒科(Parvoririnae)的病毒。
在一些实施方案中，附加体病毒是腺病毒。如本文所用，术语“腺病毒”具有其在本领域中的一般含义，并且是指腺病毒科的成员，其为中等大小(90-100nm)的无包膜(没有外部脂质双层)病毒，具有含有双链DNA基因组的二十面体核衣壳。特别地，人腺病毒包括A-F亚属及其个体血清型。A-F亚属包括但不限于人腺病毒1、2、3、4、4a、5、6、7、8、9、10、11(Ad11A和Ad11P)、12、13、14、15、16、17、18、19、19a、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、34a、35、35p、36、37、38、39、40、41、42、43、44、45、46、47、48和91型。
在一些实施方案中，附加体病毒是疱疹病毒。如本文所用，术语“疱疹病毒”具有其在本领域中的一般含义，并且是指疱疹病毒科的成员，该科的名称源自希腊语单词herpein(“爬行(to creep)”)，是指这组病毒典型的潜伏性的反复感染。疱疹病毒的实例包括但不限于伊洛病毒属(Iltovirus)；长鼻动物病毒属(Proboscivirus)；巨细胞病毒属(Cytomegalovirus)；马立克病毒属(Mardivirus)；细长病毒属(Rhadinovirus)；玛卡病毒属(Macavirus)；玫瑰疹病毒属(Roseolovirus)；单纯疱疹病毒属(Simplexvirus)；盾板病毒属(Scutavirus)；水痘病毒属(Varicellovirus)；马疱疹病毒属(Percavirus)；淋巴隐病毒属(Lymphocryptovirus)；鼠巨细胞病毒属(Muromegalovirus)。特别地，本发明的方法特别适用于根除单纯疱疹病毒-1(HSV-1)、单纯疱疹病毒-2(HSV-2)、水痘带状疱疹病毒(VZV)、Epstein-Barr病毒(EBV)、淋巴细胞病毒、巨细胞病毒(CMV)、玫瑰病毒、疱疹淋巴细胞病毒和卡波西氏肉瘤相关的疱疹病毒的持久性。
在一些实施方案中，附加体病毒是乳头瘤病毒。如本文所用，术语“乳头瘤病毒”涉及来自乳头瘤病毒科病毒的DNA病毒，其感染哺乳动物的皮肤和粘膜。对于人PV(HPV)，已经描述了超过110种HPV基因型(de Villiers,E.M.,C.Fauquet,T.R.Broker,H.U.Bernard,and H.zur Hausen.2004.Classification of papillomaviruses.Virology 324:17-27)。已知大约50种HPV基因型感染粘膜。这些粘膜基因型根据其与癌症的流行病学关联分为三个不同的组：“低风险”人乳头瘤病毒(LR-HPV)、“高风险”人乳头瘤病毒(HR-HPV)和“推定的高风险”人乳头瘤病毒(pHR-HPV)。还已知HR-HPV可引起外阴、肛门、阴道、阴茎和口咽癌，以及阴道上皮内瘤变、肛门上皮内瘤变、外阴上皮内瘤变和阴茎上皮内瘤变。优选地，HPV是粘膜HPV；更优选地，本发明的HPV是高风险HPV基因型(HR-HPV)，其是发生宫颈癌的主要病因，更优选HPV是HPV 31、33、35、39、45、51、52、56、58、59、68、73和82，最优选HPV16或HPV18。
在一些实施方案中，附加体病毒是多瘤病毒。如本文所用，术语“多瘤病毒”具有其在本领域中的一般含义，并且是指多瘤病毒科的成员，该科病毒的天然宿主主要是哺乳动物和鸟类。在人中发现了9种多瘤病毒：JCV、BKV、KI病毒和WU病毒，Merkel细胞多瘤病毒(MCV)、Trichodyssia sinulosa相关的多瘤病毒(TSV)、HPyV6、HPyV7和HPyV9。在这些人多瘤病毒中，JCV、BKV和MCV引起严重的并发症和疾病。在一些实施方案中，本发明的方法特别适用于根除BKV的持久性。如本文所用，术语“BK病毒”或“BKV”具有其在本领域中的一般含义，并且是指已知的4种BKV血清型(血清型I-IV；例如，Knowles等,J.Med.Virol.28:118-123,1989)。
在一些实施方案中，附加体病毒是细小病毒。如本文所用，术语“细小病毒”是指属于细小病毒科，优选来自细小病毒亚科的成员的病毒。示例性细小病毒包括但不限于猫泛白细胞减少症病毒、2型犬细小病毒、人细小病毒B19、小鼠微小病毒、牛细小病毒、犬细小病毒、鸡细小病毒和鹅细小病毒。
在一些实施方案中，附加体病毒是逆转录病毒。如本文所用，术语“逆转录病毒”具有其在本领域中的一般含义，并且是指逆转录病毒科的成员，其是具有DNA中间体并且靶向宿主细胞的单链正义RNA病毒。逆转录病毒的实例包括但不限于牛慢病毒(例如，牛免疫缺陷病毒、Jembrana病病毒)、马慢病毒(例如马感染性贫血病毒)、猫慢病毒(例如猫免疫缺陷病毒)、绵羊/山羊慢病毒(例如，山羊关节炎-脑炎病毒、绵羊慢病毒、维斯纳病毒)和灵长类动物慢病毒，例如人类免疫缺陷病毒(HIV)，包括1型人类免疫缺陷病毒(HIV-1)、2型人类免疫缺陷病毒(HIV-2)、3型人类免疫缺陷病毒(HIV-3)；猿猴AIDS逆转录病毒SRV-1，包括4型人T细胞淋巴细胞病毒(HIV-4)和猿猴免疫缺陷病毒(SIV)、劳氏肉瘤病毒、禽白血病病毒、和禽成髓细胞瘤病毒、禽癌肿病毒-米尔希尔2株，禽细胞瘤病毒29、禽肉瘤病毒CT10、Fujinami肉瘤病毒、UR2肉瘤病毒、Y73肉瘤病毒、Jaagsiekte绵羊逆转录病毒、叶猴病毒、Mason-Pfizer猴病毒、松鼠猴逆转录病毒、小鼠乳腺肿瘤病毒、鼠白血病病毒、猫白血病病毒、猫肉瘤病毒、长臂猿白血病病毒、豚鼠C型肿瘤病毒、猪C型致癌病毒、Finkel-Biskis-Jinkins鼠肉瘤病毒、Gardner-Arnstein猫肉瘤病毒、Hardy-Zuckerman猫肉瘤病毒、Harvey鼠肉瘤病毒、Kirsten鼠肉瘤病毒、Moloney鼠肉瘤病毒、Snyder-Thei猫肉瘤病毒、羊毛猴肉瘤病毒；禽网状内皮细胞增生病毒，包括但不限于小鸡合胞体病毒、网状内皮细胞增生病毒和Trager鸭脾坏死病毒、牛白血病病毒和人T淋巴细胞病毒。
在一些实施方案中，本发明的附加体病毒不感染受试者的肠或肝细胞。
如本文所用，术语“持续存在”或“持久性”是指附加体病毒在受试者中维持的能力。减少病毒持久性的意义在于，病毒引起的直接症状也将被消除，以及与病毒感染相关的某些事件或病症也将被消除。
如本文所用，术语“表达”是指将DNA病毒基因组转录成病毒RNA(信使或前基因组)，并合成病毒蛋白和产生感染性颗粒的能力。
因此，本发明的方法特别适用于治疗由上述附加体病毒介导的病毒感染。特别地，本发明的方法特别适用于治疗活动性、潜伏性或再活化的感染。如本文所用，“活动性感染”是指附加体病毒在细胞中复制。“附加体病毒的再活化”是指在具有潜伏性感染的受试者中发生活动性感染。如本文所用，“潜伏性感染”是指非活动性的感染。具有或疑似具有潜伏性感染的受试者包括已暴露于附加体病毒的受试者，和/或临床上已检测到附加体病毒DNA和/或抗病毒抗体的存在的受试者。
如本文所用，术语“治疗”是指预防性或防护性治疗以及治愈性或疾病改良性治疗，包括治疗处于感染疾病风险或疑似感染疾病的患者以及生病或被诊断为患有疾病或医学病症的患者，并包括抑制临床复发。治疗可以施用于患有医学病症或最终可能患有病症的受试者，以便预防、治愈、延迟病症或复发病症的一种或多种症状的发作、降低病症或复发病症的一种或多种症状的严重性或改善病症或复发病症的一种或多种症状，或者为了将受试者的生存期延长超过在没有这种治疗的情况下预期的生存期。“治疗方案”是指疾病的治疗模式，例如治疗期间使用的剂量模式。治疗方案可包括诱导方案和维持方案。短语“诱导方案”或“诱导期”是指用于疾病初始治疗的治疗方案(或治疗方案的一部分)。诱导方案的总体目标是在治疗方案的初始阶段向患者提供高水平的药物。诱导方案可以采用(部分或全部)“加载方案”，其可以包括施用比医生在维持方案期间使用的更大剂量的药物，比医生在维持方案期间所施用的更频繁地施用药物，或两者。短语“维持方案”或“维持期”是指在治疗疾病期间用于维持患者的治疗方案(或治疗方案的一部分)，例如，使患者长期保持缓解(几个月或几年)。维持方案可以采用持续治疗(例如，以规律的间隔(例如，每周、每月、每年等)施用药物)或间歇治疗(例如，中断治疗、间歇治疗、复发时的治疗或实现特定的预定标准[例如，疾病临床表现等]时的治疗)。
本发明的方法可以用任何受试者进行。受试者优选为哺乳动物，更优选为灵长类动物，更优选为人。受试者可以是男性或女性，并且可以是任何年龄，包括胎儿(即，在子宫内)、新生儿、婴儿、少年、青年、成人和老年受试者。因此，在一些情况下，受试者可以是怀孕的女性受试者。
在一些实施方案中，受试者患有或疑似患有潜伏性感染。在一些实施方案中，受试者已被诊断患有活动性感染。
在一些实施方案中，受试者是免疫功能不全的。免疫功能不全的个体包括但不限于AIDS患者；慢性免疫抑制治疗方案的患者，如器官移植患者；霍奇金病或淋巴瘤等癌症患者；以及患有自身免疫病症并正在用以下治疗的患者：替麦考酚酯或生物制剂如那他珠单抗、利妥昔单抗或依法珠单抗。此类自身免疫病症包括但不限于多发性硬化症(MS)、类风湿性关节炎(RA)和系统性红斑狼疮(SLE)。具有或疑似具有潜伏性多瘤病毒感染的免疫系统较弱的老年患者也有发生与多瘤病毒相关的疾病的风险。
在一些实施方案中，受试者患有癌症并且施用细胞消融治疗如化疗或放疗。如本文所用，术语“癌症”具有其在本领域中的一般含义，并且包括但不限于实体瘤和血源性肿瘤。术语“细胞消融治疗”具有其在本领域中的一般含义，并且是指通过几种不同机制对快速增殖细胞的细胞诱导消融效果的疗法，其最终导致细胞周期停滞和/或细胞凋亡。通常，细胞消融治疗包括化疗和放疗。如本文所用，术语“放疗”具有其在本领域中的一般含义，并且是指电离辐射的医学用途，通常作为癌症治疗的一部分来控制或杀死恶性细胞。如本文所用，术语“化疗”具有其在本领域中的一般含义，并且是指有效抑制肿瘤生长的化疗剂的医学用途。
在一些实施方案中，受试者是施用免疫抑制剂的移植受试者。在一些实施方案中，移植受试者具有至少一种选自肾、骨髓、肝、肺、胃、骨、睾丸、心脏、胰腺和肠的移植器官。在一些实施方案中，对于需要免疫抑制剂的受试者，本文所述的化合物可与免疫抑制剂组合(同时或顺次)施用。如本文所用，术语“免疫抑制剂”是指抑制或阻止受试者免疫系统活性的任何试剂。免疫抑制剂的非限制性实例包括特异性结合CD20、CD25(例如巴利昔单抗或达珠单抗)或CD3(例如，莫罗莫那单抗)的抗体(例如，完全人或人源化抗体)；钙调神经磷酸酶抑制剂(例如，环孢菌素、吡美莫司、他克莫司、西罗莫司和/或环孢菌素)；干扰素(例如，干扰素-β)；类固醇(例如，本领域已知的或本文所述的任何类固醇)；白细胞介素-1受体拮抗剂；替麦考酚酯；
硫唑嘌呤；甲氨蝶呤；和/或TNF-α结合蛋白(例如，抗体和/或可溶性TNF-α受体，例如英夫利昔单抗、依那西普和/或阿达木单抗)。
在一些实施方案中，本发明的方法特别适用于在高度活性抗逆转录病毒治疗(HAART)后根除HIV储库。如本文所用，术语“储库”是指存在于静息CD4+T细胞中的潜伏性但可复制的HIV-1原病毒。如本文所用，术语“HAART”具有其在本领域中的一般含义，并且是指任何高度活性抗逆转录病毒疗法，并且最近被称为组合抗逆转录病毒疗法，或“cART”，在本文中可与“CART”互换使用。HAART和cART在本文中也可互换使用。HAART可以指组合使用的三种或更多种抗逆转录病毒药物，并且通常包含一种蛋白酶抑制剂和两种或三种逆转录酶抑制剂。
如本文所用，术语“FXR”具有其在本领域中的一般含义，并且是指法尼酯X受体，其是由超生理水平的法尼醇激活的核受体(Forman等,Cell,1995,81,687-693)。FXR也称为NR1H4、类视黄醇X受体相互作用蛋白14(RIP14)和胆汁酸受体(BAR)。FXR包含保守的DNA结合结构域(DBD)和C末端配体结合结构域(LBD)，可与多种天然存在的胆汁酸(BA)结合并被其激活，所述胆汁酸包括原代胆汁酸鹅去氧胆酸(CDCA)及其牛磺酸和甘氨酸偶联物(Makishima等,1999；Parks et al.,1999；Wang et al.,1999)。FXR的人多肽序列以登录号NM_005123、Q96RI1、NP_005114、AAM53551、AAM53550、AAK60271保存在核苷酸和蛋白质数据库中。
如本文所用，术语“FXR激动剂”具有其在本领域中的一般含义，并且特别是指通过靶向和选择性结合法尼酯X受体(FXR)起作用并且使FXR活化比Maloney等描述的测定法(J.Med.Chem.2000,43:2971-2974)中的背景高至少40％的化合物。在一些实施方案中，本发明的FXR激动剂是选择性FXR激动剂。如本文所用，术语“选择性FXR激动剂”是指FXR激动剂，其与由LXRα、LXRβ、PPARα、PPARγ、PPARδ、RXRα、RARγ、VDR、SXR、ERα、ERβ、GR、AR、MR和PR组成的一组核受体中的一个或多个(理想地基本上全部)不显示显著的交叉反应性。测定显著交叉反应性的方法描述于J.Med.Chem.2009,52,904-907。
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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激动剂的种类。
在一些实施方案中，FXR激动剂选自小分子化合物，其作为已在以下专利公布文件中公开的FXR调节剂：EP1392714；EP1568706；EP2128158,EP2289883,JP2005281155；US20030203939；US2005080064；US2006128764；US20070010562；US20070015796；US20080038435；US20080300235；US20090062526,US20090163552,US20100093818,US20100184809；US20110077273,US20110105475；US6984560；US7671085；WO2000037077；WO200040965；WO200076523；WO2001017994；WO2003015771；WO2003016280；WO2003016288；WO2003030612；WO2003060078；WO2003080803；WO2003090745；WO2004007521；WO2004046162；WO2004048349；WO2005082925；WO2005092328；WO2005097097；WO2006020680；WO2007076260；WO2007076260；WO2007092751；WO2007140174；WO2007140183；WO2008000643；WO2008002573；WO2008025539；WO2008025540；WO2008051942；WO2008073825；WO2008157270；WO2009005998；WO2009012125,WO2009027264；WO2009062874；WO2009080555；WO2009127321；WO2009149795,WO2010028981；WO2010034649；WO2010034657；WO2010069604；WO2011020615；WO2013007387和WO2013037482。
FXR激动剂的具体实例包括但不限于GW4064(如PCT公开号WO 00/37077或US2007/0015796中所公开的)、6-乙基-鹅去氧胆酸(6ECDCA)，尤其是3α,7α-二羟基7α-二羟基-6α-乙基-5β-胆烷-24-酸，也称为INT-747；6-乙基熊去氧胆酸、INT-1103、UPF-987、WAY-362450、MFA-1、GW9662、T0901317、fexaramine、胆酸、脱氧胆酸、甘氨胆酸、甘氨脱氧胆酸、牛磺胆酸、牛磺酸二氢呋喃酯、牛磺酸脱氧胆酸、胆酸盐、甘氨胆酸盐、脱氧胆酸盐、牛磺胆酸盐、牛磺脱氧胆酸盐、鹅去氧胆酸、7-B-甲基胆酸、石胆酸甲酯。
在一些实施方案中，FXR激动剂选自GW4064、6ECDCA和由CAS REGISTRY NUMBER1192171-69-9鉴定的化合物(描述于WO2009127321，也称为PXL007)：
在一些实施方案中，FXR激动剂是具有下式的化合物：
在一些实施方案中，FXR激动剂是具有下式的化合物：
在一些实施方案中，FXR激动剂是具有下式的化合物：
在一些实施方案中，FXR激动剂是奥贝胆酸(缩写为OCA)，其是半合成胆汁酸类似物，化学结构为6α-乙基-鹅去氧胆酸。该化合物也称为INT-747。
在一些实施方案中，FXR激动剂选自下组：
在一些实施方案中，FXR激动剂选自WO2013007387中公开的化合物，即：
在一些实施方案中，FXR激动剂选自WO2009149795中公开的化合物，即：
在一些实施方案中，FXR激动剂选自WO2008025539中公开的化合物，即：
在一些实施方案中，FXR激动剂选自WO2008025540中描述的化合物，即：
本领域技术人员可基于如PCT/US99/30947(其教导通过引用以其整体并入本文)中所述的测定法常规鉴定可用于本发明的另外的FXR激动剂。通常，使用核受体-肽测定法鉴定FXR激动剂。该测定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结合FXR。FRET测定法基于以下原理：配体诱导核受体的构象变化，促进与转录激活所需的共激活蛋白的相互作用。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到受体分子(其通常是荧光分子)。或者，在包含一个或几个拷贝的典型的共有FXR反应元件的启动子控制下，通过监测这些配体对报告基因表达的影响来鉴定FXR配体的活性。随后的分析依赖于质粒构建体，该质粒构建体在报告基因(通常是荧光素酶基因)前面包含启动子，并且可以在细菌中容易地扩增并在哺乳动物细胞中转染。该测定法可以全面评估配体对FXR转录活性的影响，其可以是积极的(激动剂)或消极的(拮抗剂)。
通常，本发明的FXR激动剂以治疗有效量向受试者施用。如上所述的“治疗有效量”的FXR激动剂是指足够量的FXR激动剂以适用于任何医学治疗的合理的收益/风险比治疗病毒感染。然而，应该理解，本发明化合物和组合物的每日总用量将由主治医师在合理的医学判断范围内决定。任何特定患者的特定治疗有效剂量水平将取决于多种因素，包括所治疗的病症和病症的严重程度；所用特定化合物的活性；所用的具体组合物；患者的年龄、体重、总体健康状况、性别和饮食；施用时间、施用途径和所用特定化合物的排泄率；治疗的持续时间；与所用特定激动剂组合使用的药物；以及医学领域众所周知的因素。例如，本领域众所周知以低于实现所需治疗效果所需的水平开始化合物的剂量并逐渐增加剂量直至达到所需效果。然而，产品的日剂量可在每个成人每天0.01-1,000mg的宽范围内变化。优选地，组合物包含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活性成分，用于对待治疗患者的剂量进行症状调整。药物通常包含约0.01mg-约500mg活性成分，优选1mg-约100mg活性成分。通常以每天0.0002mg/kg-约20mg/kg体重，特别是每天约0.001mg/kg-7mg/kg体重的剂量水平提供有效量的药物。
本发明的FXR激动剂可以与药学上可接受的赋形剂和任选的缓释基质(例如可生物降解的聚合物)组合以形成治疗组合物。“药学上”或“药学上可接受的”是指当适当地施用于哺乳动物，尤其是人时，不产生不利、过敏或其他不良反应的分子实体和组合物。药学上可接受的载体或赋形剂是指无毒的固体、半固体或液体填充剂、稀释剂、包封材料或任何类型的制剂助剂。在本发明的用于口服、舌下、皮下、肌肉内、静脉内、透皮、局部或直肠施用的药物组合物中，单独或与另一种活性成分组合的活性成分可以以单位施用形式，作为与常规药物支持物的混合物，向动物和人类施用。合适的单位施用形式包括口服途径形式，例如片剂、凝胶胶囊、粉末、颗粒和口服悬浮液或溶液、舌下和口腔施用形式、气雾剂、植入物、皮下、透皮、局部、腹膜内、肌肉内、静脉内、真皮下、透皮、鞘内和鼻内施用形式和直肠施用形式。可以对小肠或结肠中的特定递送进行盖伦适应。优选地，药物组合物包含对于能够注射的制剂而言药学上可接受的载体。这些特别可以是等渗的、无菌的盐溶液(磷酸一钠或磷酸二钠、氯化钠、氯化钾、氯化钙或氯化镁等或这些盐的混合物)、或干燥的，特别是冷冻干燥的组合物，其允许根据情况添加无菌水或生理盐水时构成可注射溶液。适于注射使用的药物形式包括无菌水溶液或分散体；包括芝麻油、花生油或丙二醇水溶液的制剂；和用于临时制备无菌注射溶液或分散体的无菌粉末。在所有情况下，该形式必须是无菌的并且必须是流动易于注射的程度。它必须在制备和储存条件下稳定，并且必须防止微生物如细菌和真菌的污染作用。包含本发明的FXR激动剂作为游离碱或药学上可接受盐的溶液可以在适当地与表面活性剂如羟丙基纤维素混合的水中制备。分散体也可以在甘油、液体聚乙二醇及其混合物中和油中制备。在普通的储存和使用条件下，这些制剂含有防腐剂以防止微生物的生长。本发明的FXR激动剂可以配制成中性或盐形式的组合物。药学上可接受的盐包括酸加成盐(与蛋白质的游离氨基形成)，其与无机酸例如盐酸或磷酸，或有机酸如乙酸、草酸、酒石酸、扁桃酸等形成。与游离羧基形成的盐也可以衍生自无机碱，例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁，和有机碱，如异丙胺、三甲胺、组氨酸、普鲁卡因等。载体也可以是溶剂或分散介质，其包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)、其合适的混合物和植物油。例如，通过使用诸如卵磷脂的包衣，在分散体的情况下通过保持所需的粒径和通过使用表面活性剂，可以保持适当的流动性。可以通过各种抗细菌剂和抗溶解剂(antifusoluble agent)，例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等来防止微生物的作用。在许多情况下，优选包括等渗剂，例如糖或氯化钠。通过在组合物中使用延迟吸收的试剂，例如单硬脂酸铝和明胶，可以实现可注射组合物的延长吸收。通过将所需量的活性多肽与上文列举的各种其他成分(如果需要)加入适当的溶剂中，然后过滤灭菌，来制备无菌可注射溶液。通常，通过将各种灭菌的活性成分加入无菌载体中来制备分散体，所述无菌载体包含基础分散体介质和所需的来自上文列举的其他成分。在用于制备无菌可注射溶液的无菌粉末的情况下，优选的制备方法是真空干燥和冷冻干燥技术，其从之前无菌过滤的溶液中产生活性成分和任何其他所需成分的粉末。一旦配制，溶液将以与剂量制剂相容的方式并以治疗有效的量施用。制剂易于以多种剂型施用，例如上述可注射溶液的类型，但也可使用药物释放胶囊等。例如，对于水溶液中的肠胃外施用，如果需要，溶液应适当缓冲，并且首先用足够的盐水或葡萄糖使液体稀释剂等渗。这些特定的水溶液特别适用于静脉内、肌肉内、皮下和腹膜内施用。就此而言，根据本公开内容，可以使用的无菌水性介质对于本领域技术人员而言将是已知的。例如，可以将一个剂量溶解在1ml等渗NaCl溶液中，并将其添加到1000ml的皮下注射液中或所建议的输注部位注射。取决于所治疗的受试者的情况，剂量必然发生一些变化。在任何情况下，负责施用的人员将确定个体受试者的适当剂量。本发明的FXR激动剂可以在治疗混合物中配制成每剂量包含约0.0001-1.0毫克，或约0.001-0.1毫克，或约0.1-1.0或甚至约10毫克。也可以施用多剂量。除了配制用于肠胃外施用例如静脉内或肌内注射的本发明的FXR激动剂，其他药学上可接受的形式包括，例如，用于口服施用的片剂或其他固体；脂质体制剂；时间释放胶囊；以及目前使用的任何其他形式。
将通过以下附图和实施例进一步说明本发明。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。
附图说明
图1：FXR配体对H9细胞系增殖和细胞死亡的影响。H9细胞以1x 106个细胞/mL开始在标准RPMI1640中生长，并且用或不用10μM的GW4064或Takeda处理，或仅用DMSO载体处理。通过Cellometer Nexcelom Auto 1000装置每周三次测定细胞计数和活力后，取出一定体积的细胞培养物(细胞和培养基)并用含有分子的新鲜培养基替换以将细胞浓度维持为约1x 106个细胞/mL。细胞增殖由细胞增殖因子定义，该细胞增殖因子计算为在每次培养基更换时来自一个接种细胞的细胞数(上图)。在培养基中释放的LDH活性的剂量监测细胞死亡率(下图)。
图2：FXR配体对活化的PBMC存活和死亡的影响。将PHA/IL2活化的PBMC以1x 106个细胞/mL接种于补充有IL2的标准RPMI1640中，并且用或不用10μM的GW4064或Takeda处理，或仅用DMSO载体处理，并保持一周。取等分试样并使用Cellometer Nexcelom Auto 1000装置计数细胞，并在每次培养基更换时计算细胞增殖因子，如图1所示(上图)。在培养基中释放的LDH活性的剂量监测细胞死亡率(下图)。
图3：FXR配体对HIV-1感染的H9细胞中细胞活力和p24产量的影响。将3千万个H9细胞在标准RPMI中的10mL 1/100稀释的HIV-1NL4.3病毒原液中孵育6小时。然后将细胞在RPMI中洗涤两次，并在标准RPMI中以1x 106个细胞/mL接种，并在10mL培养物中用10μM的GW4064或Takeda处理，或仅用DMSO载体处理。在指定的时间，通过Cellometer NexcelomAuto 1000装置测定细胞计数和活力，并取出一定体积的细胞培养物(细胞和培养基)并用含有分子的新鲜培养基替换以将细胞浓度维持为约1x 106个细胞/mL。在每次培养基更换时计算由来自一个接种细胞的细胞数定义的细胞增殖。将取出的无细胞培养基储存在-20℃直至感染滴度测定和p24剂量。上图和中图分别显示感染后指定时间的每种情况的细胞增殖和细胞活力百分比，下图显示p24的累积产量。
图4：FXR配体对HIV-1感染的H9细胞的HIV-1病毒产量的影响。如图3所示制备和处理细胞。上图和中图分别显示用对数或线性Y标度绘制的在感染后指定时间的每种情况下的感染后滴度、每mL无细胞培养基的实际感染性颗粒数。下图显示每ng p24的感染性颗粒的比例。
图5：在感染的H9细胞中FXR激动剂GW4064对HIV-1复制的剂量反应。如图3所示处理和感染细胞，并测试在指定时间0.2、1和5μM的GW4064和仅DMSO载体对细胞活力(A)、感染性病毒粒子的产量、感染滴度(B)和由每ng p24的感染单位比例定义的特定感染性(C)的影响。
图6：在来自一个供体的活化PBMC中FXR配体对HIV-1复制的影响。将3千万个PHA和IL2活化的PBMC在标准RPMI中的10mL1/100稀释的HIV-1NL4.3病毒原液中孵育6小时。然后将细胞在RPMI中洗涤两次，并在补充有IL2的标准RPMI中以1x 106个细胞/mL接种，并用10μM的GW4064或Takeda处理，或仅用DMSO载体处理。在感染后的指定时间对等分试样取样并储存在-20℃直至感染滴度测定和p24剂量。上图显示总细胞计数随时间的变化，其对于所有条件都保持稳定。中图显示在指定时间p24的累积产量，下图显示以每mL感染颗粒表示的感染滴度。
图7：在来自第二供体的活化PBMC中FXR配体对HIV-1复制的影响。如图6所示处理活化的PBMC，除了在第7天添加补充有IL2和指定分子的新鲜RPMI。上图显示总细胞计数随时间和指示的FXR配体或载体的变化。中图显示三种实验条件下细胞活力的变化，下图显示具有对数Y标度的p24产量。
图8：H9和PBMC表达FXR。通过蛋白质印迹分析H9和新鲜或PHA-IL2活化的PBMC的全部裂解物中FXR的存在。将相同量的细胞裂解物加载在凝胶上，肌动蛋白染色显示相似强度的肌动蛋白条带。在H9和活化的PBMC裂解物中检测到对应于FXR的条带，但在新鲜的PBMC中仅微弱地检测到。H9中的FXR表达似乎高于PBMC。
图9：用shFXR慢病毒载体产生FXR沉默的H9细胞系。用shFXR慢病毒载体转导细胞，并如材料和方法章节中所述进行选择。将转导细胞和对照细胞在存在或不存在10μMGW4064的情况下培养3天。然后裂解细胞并通过蛋白质印迹分析FXR表达。FXR表达显著降低并且被FXR激动剂GW4064进一步抑制。
图10：H9细胞中的FXR沉默抑制FXR激动剂对HIV-1NL4.3复制的影响。将shFXR和shCont H9细胞用1/100稀释的NL4.3病毒原液感染6小时。然后洗涤细胞并以1x 106个细胞/mL接种补充有仅载体或1μM和5μM的GW4064的新鲜培养基(用于测定感染滴度)。在指定的天数计数细胞，并从每种条件下取出计算体积的细胞悬浮液，以将细胞浓度保持为约1x106/mL。向细胞瓶中添加等体积的含有分子的新鲜培养基。对于每种条件，在每个时间点测定p24浓度(A)和HIV滴度(B)。p24和HIV滴度以在4天、7天和9天相对于DMSO处理的shContH9中测定的值表示。条形图上方的星号数反映统计p值；**p<0.01,***p<0.001和****p<0.0001。
图11：FXR激动剂GW4064对潜伏性感染的8.4和15.4J-Lat克隆的影响。将每个细胞包含一个沉默的整合原病毒拷贝的8.4和15.4克隆仅用0.5ng/mL的TNFα刺激或用0.5ng/mL的TNFα与5μM的FXR激动剂GW4064或6ECDCA的组合刺激。通过流式细胞术定量由于原病毒再激活而表达GFP的细胞比例(A1和A2)。细胞活力和p24产量分别显示于图B1和B2以及C1和C2中。
图12：FXR激动剂GW4064抑制RPTEC中的BKV复制。将RPTEC细胞以5x104个细胞/孔接种在24孔板中，并保持在不含补充物的REBM加2％FCS中。用BKV原液稀释液(1/100)感染细胞4小时，然后在DMEM中洗涤。添加1mL/孔的REBM加2％FCS和GW4064或载体。在感染后第3天和第5天通过qPCR监测细胞上清液中的BKV产生。与感染后两天的模拟处理的细胞相比，用10μM的GW4064处理使上清液中的病毒滴度降低超过1.5Log10(p<1x10-4)。标准偏差小于2％，然后在标记内。
具体实施方式
材料和方法
细胞系
H9细胞系是选择用于允许HIV-1复制的T淋巴瘤Hut 78细胞系的克隆衍生物。在37℃、5％CO2下，在补充有10％胎牛血清、非必需氨基酸和抗生素的RPMI-1640培养基(标准RPMI)中以0.5-1.5x 106个细胞/mL的浓度生长细胞。
HEK293T是人胚胎肾293细胞系的衍生物，其中插入了SV40 T-抗原的温度敏感基因。在37℃、5％CO2下，将HEK293T细胞系维持在补充有10％胎牛血清的Dulbecco改良的Eagle培养基(DMEM)中。
Vero细胞系来自正常成年非洲绿猴的肾脏。在37℃、5％CO2下，将Vero细胞维持在补充有10％胎牛血清的Dulbecco改良的Eagle培养基(DMEM)中。
在37℃、5％CO2下，将表达人CD4和CXCR4的HeLa-P4细胞，HeLa CD4+HIV-1LTR-β-gal细胞(MAGI)维持在补充有10％胎牛血清的DMEM中(1)。
之前称为JC53-bl(克隆13)的TZM-bl是HeLa细胞系。亲本细胞系(JC.53)稳定表达大量CD4和CCR5。通过在HIV-1启动子控制下引入单独的整合拷贝的荧光素酶和β-半乳糖苷酶基因，从JC.53细胞产生TZM-bl细胞系。TZM-bl细胞系对多种HIV-1分离株的感染高度敏感。在37℃、5％CO2下，将细胞维持在补充有10％胎牛血清的DMEM中。
潜伏性的HIV感染克隆8.4和15.4来源于用全长HIV基因组转染的潜伏性jurkat群体，其表达绿色荧光蛋白，但不表达HIV，但可被佛波醇酯或TNFα转录激活(2)。
从Lonza(瑞士)获得原代人肾近端小管上皮细胞(RPTEC)。RPTEC分离自人肾近端小管，是来自皮层和肾小球的上皮细胞的混合物。按照提供者的方案，在来自Lonza(瑞士)的包含补充物和生长因子(氢化可的松、hEGF、FBS、肾上腺素、胰岛素、三碘甲腺原氨酸、转铁蛋白和庆大霉素/两性霉素-B)的肾上皮基础培养基(REBM)中培养细胞。
根据制造商的推荐，用Cellometer Nexcelom Auto 1000(Bioscience)通过台盼蓝染色排除法来测量细胞活力和计数。
通过用细胞毒性检测试剂盒PLUS(Roche)测量细胞培养基中释放的胞内乳酸脱氢酶(LDH)的活性来监测细胞死亡。
制备人外周血单核细胞
人外周血单核细胞(PBMC)由在“Etablissement
du Sang”Lyon收集的健康供体的献血制备。简言之，将等体积的含1mM EDTA的PBS加入血液中。然后将35mL稀释的血液在50mL管中的15mL Ficoll(Eurobio)上分层，并在20℃和625g下离心20分钟。收集界面处的PBMC细胞环，在PBS中洗涤3次。然后在Percoll梯度(GE Healthcare)上运行PBMC；将3mL PBMC(25-30x 106个细胞/mL)在15mL管中的6mL Percoll 50％上分层。在20℃和770g离心20分钟后，收集主要由T和B淋巴细胞和NK细胞组成的沉淀，在PBS中洗涤两次，重悬并在补充有10％胎牛血清、非必需氨基酸(NEAA)和抗生素的RPMI 1640(标准培养基)中调节至1x106个细胞/mL。
淋巴细胞活化
将1x106个细胞/mL的PBMC在补充有PHA 10μg/mL和IL2 20U/mL的标准培养基中活化48小时。然后以1x106个细胞/mL用含有20U/mL IL2的标准培养基替换培养基。然后在感染和处理期间将刺激的淋巴细胞维持在含有20U/mL IL2的标准培养基中。
慢病毒载体、shRNA和shFXR和shContFXR H9细胞系的产生
将HEK293T细胞铺板在涂有0.01％L-聚赖氨酸(P4832 Sigma)的10cm培养皿上，并用含有8μg pPAX2、4μg pVSVG和10μg pLKO.1-puro-shFXR或10μg对照pLKO.1-puro-shMafG的质粒混合物和2.5M CaCl2以50％汇合率转染(表1)。6小时后洗涤细胞，用还原的血清培养基(Opti-MEM,Thermo Fisher Scientific)替换培养基40小时。通过在Vivaspin 20(VS2042 Sartorius)中以4500rpm离心20分钟，从澄清的上清液(0.45μm过滤器)浓缩慢病毒颗粒。
在用浓缩的shControl或shFXR慢病毒颗粒铺板后三天，将H9细胞转导24小时。然后洗涤细胞，用完全RPMI培养基更换培养基24小时。第二天，用含有3μg/ml嘌呤霉素的标准培养基替换培养基。保持3μg/ml嘌呤霉素选择直至实验结束。
病毒
质粒pNL4-3是T细胞向性分离株NL4-3的感染性分子克隆(3)。按照制造商的程序，使用JetPEI Polyplus-Transfection(Ozyme)试剂，在用质粒DNA转染的HEK 293T细胞中制备病毒原液。将转染后第3天的含病毒上清液通过离心(1,000×g,5min)澄清，并通过0.45μm孔径的过滤器过滤以除去残留的细胞和碎片。将病毒原液等分，储存在-20℃并用标准方法在MAGI细胞上解冻后滴定。
如(4)中所述，在Vero细胞中扩增多瘤病毒BKV株Dunlop。通过qPCR,BK Virus R-
Argene(bioMérieux)进行原液病毒滴定，并以1x1011基因组当量/mL测量。
化学品
GW4064[3-(2,6-二氯苯基)-4-(3-羧基-2-氯-芪-4-基)-氧甲基-5-异丙基异恶唑]是FXR激动剂(EC50 90nM)，在体内和体外均有活性(5)。虽然GW4064显示有限的生物利用度，但作为一种强大的选择性FXR配体已广泛使用，并已在该领域达到“参考化合物”的地位。6-ECDCA(6-乙基-鹅-脱氧胆酸)是胆汁盐衍生物和强FXR激动剂(EC50 99nM)，并且获得自Sigma-Aldrich(6)。合成的FXR拮抗剂CAS936123-05-6，在此称为Takeda(描述于专利WO2007052843 A1 20070510；Takeda Pharmaceuticals，Osaka，Japan)，由Edelris，Lyon，France合成。将这些化合物以10mM溶解于DMSO中。凝集素来自腰豆(phasolus vulgaris)(PHA-M)，人重组白细胞介素2(IL-2)和TNFα购自Sigma-Aldrich。
蛋白质印迹
用PBS洗涤细胞(H9和PBMC)并沉淀。将细胞沉淀在4℃下溶解于裂解缓冲液(Tris-HCl(pH 7,4),EDTA 1mM,NaCl 180mM,0,5％NP-40和蛋白酶抑制剂)中20分钟。然后将悬浮液在4℃下以17000g离心20分钟以制备全细胞提取物。通过Bradford测定法测定蛋白质浓度。
将细胞裂解物加载到1x MES缓冲液(
MES SDS运行缓冲液)中的4-12％Bis-Tris Mini Gel
上。在200V电泳35分钟后，按照
GelTransfer Stacks Nitrocellulose(Invitrogen)方案将蛋白质转移到硝酸纤维素膜上。将膜在PBS Tween 20 0.1％-0％脂肪乳5％中饱和2小时。然后，在室温下用1μg/ml的抗人FXR/NR1H4单克隆抗体(R&D Systems)探测膜1小时，在室温下使用Super
West-最大灵敏度底物(ThermoFisher Scientific)，与0.08μg/ml与过氧化物酶偶联的AffiniPure山羊抗小鼠IgG(Jackson ImmunoResearch Laboratories)反应1小时。
HIV-1p24定量
按照制造商的说明，使用mini VIDAS自动化装置(bioMérieux)用HIV P24 II试剂盒进行p24定量。离心培养基，通过添加等体积的含4％Tween 20的PBS，在使用前灭活无细胞上清液。
HIV-1滴定
使用MAGI细胞或TZM-bl细胞对感染细胞产生的感染单位进行滴定。简言之，将连续稀释的上清液分配到每孔含有1-4x105个MAGI细胞的24孔板中或每孔含有1-4x104个TZM-bl细胞的96孔板中。培养2天后，固定细胞并染色β-半乳糖苷酶表达，并通过显微镜检查计数蓝染色的阳性细胞。然后将感染滴度表示为每毫升上清液的感染单位。或者，对于TZM-bl细胞，培养2天后裂解细胞，并使用照度计读取化学发光活性。平行处理对照细胞上清液，从感染上清液的记录值中减去基线发光。然后将感染滴度表示为任意单位的发光活性。
结果
用FXR调节剂处理不会改变淋巴母细胞H9或PBMC细胞的存活和增殖。
首先测试FXR配体对类淋巴母细胞系H9和PHA-IL2活化的PBMC的增殖或存活的影响。暴露于10μM的FXR配体、激动剂GW4064和拮抗剂Takeda两周没有改变H9的增殖(图1上图)，也没有观察到细胞培养基中的乳酸脱氢酶(LDH)释放的显著改变(图1下图)。意外地，在GW4064存在下，释放到细胞上清液中的LDH似乎甚至更低，表明GW4064对H9细胞的保护作用。类似地，在一周观察期内，FXR配体没有改变保持稳定的活化PBMC的数量，也没有诱导细胞裂解(图2)。因此，用两种FXR配体处理都没有显著改变H9和PBMC增殖-存活或细胞死亡率。
用FXR配体处理调节淋巴母细胞系H9和PBMC中的HIV-1复制和细胞存活。
然后测试用FXR激动剂和拮抗剂处理对HIV-1NL4.3感染的淋巴母细胞系H9的影响。激动剂GW4064对H9增殖和活力具有强烈影响(图3上图和中图)；实际上，与模拟处理的细胞或用拮抗剂处理的细胞相比，细胞数和活细胞百分比显著降低。同时，GW4064处理细胞的HIV-1p24的总产量在感染后第7天到达稳定期，而在另外两种情况下持续增加(图3右图)。最后，通过感染性颗粒数/mL培养基测量的感染性滴度的动力学根据处理而变化很大。激动剂GW4064诱导感染性颗粒的快速爆发，其在第5天就可检测到，随后在初始峰值后下降(图4上图和中图)。模拟或Takeda处理的细胞的动力学显示，感染性颗粒产量增加较慢，其随后在感染后第12天达到峰值，并且水平高于激动剂处理的细胞。有趣的是(图4下图)每p24 ng的感染性颗粒数显示，GW4064处理的细胞非常早且有效地产生感染性颗粒，虽然与另外两种情况下的细胞相比感染性病毒颗粒的产量较后达到峰值并且水平较低在。总而言之，这些数据表明，FXR激动剂诱导病毒复制的短暂而有效的增强，随后很快发生大量细胞死亡。与用FXR拮抗剂或载体处理的细胞相比，这些效果总体上显著降低了病毒复制。
FXR激动剂对HIV NL4.3复制的影响是剂量依赖性的。细胞活力以剂量依赖性方式从用仅载体处理的几乎70％降低至用5μM GW4064处理时的40％(图5A)。浓度低至0.2μM足以诱导对细胞活力的影响。在第11天，所有情况下活力的反弹可能反映了未感染细胞或新一轮病毒复制之前新感染细胞的进行中的细胞增殖可影响细胞存活。与第7天的模拟处理细胞相比，在所有GW4064剂量下，增加浓度的GW4064将感染性颗粒的产量增强超过一个Log10(图5B)。然后感染性颗粒的产量以剂量依赖性方式降低至低于通过模拟处理的细胞的产量，并且在5μM时达到减去一个Log10。最后，增加GW4064浓度对特定感染性具有剂量依赖性双相效应，如通过感染性颗粒/ng p24的比例所描述的(图5C)。与模拟处理的细胞相比，首先特异性感染性在早期以剂量依赖性增加，然后在第9天和第11天急剧下降。有趣的是，随着剂量减少，下降的动力学似乎更慢。然而，整体上GW4064以剂量依赖性方式抑制HIV-1复制。
用来自健康供体的PHA-IL2活化的PBMC进行类似的实验。用从两个不同供体制备的PBMC获得的数据在此作为实施例显示。使用来自第一供体的PBMC，在感染后第7天之前不能检测到HIV-1复制，并且在第9天，GW4064处理的细胞中的HIV-1复制比其他两种情况中更显著地增加(图6)。然而，如果在GW4064处理的细胞培养物中观察到最高的p24产量，则在滴定测定的条件下没有观察到感染性病毒粒子。实际上，仅在与Takeda或载体一起孵育的细胞中检测到感染性病毒颗粒的产生。使用来自第二供体的PBMC(图7)，更早(在第7天)检测到感染，并且p24产量在感染后的同一天达到比第一供体更高的水平。值得注意的是，与其他情况相比，用Takeda处理延迟了p24的产生。有趣的是，观察期间PBMC的数量仅在存在GW4064时随时间降低，并且当用FXR激动剂处理培养物时，活细胞百分比的降低更为重要。这些数据表明，用GW4064处理与HIV-1感染的PBMC中更高的细胞死亡率相关。同样，在测定条件下，仅在模拟或Takeda处理的培养物中检测到感染性颗粒，而在用GW4064处理的培养物中未检测到(未显示)。两个供体之间复制动力学的差异可能反映了供体细胞对HIV-1感染的允许性的变化。总之，这些数据证实了用H9细胞系获得的那些数据，p24产量在早期快速增加，然后是细胞死亡，和总体上感染性颗粒的产量强烈减少。
H9和PBMC表达FXR
FXR在肝脏、肠道和肾上腺中高度表达。它也在肾近端小管上皮细胞中高表达(7,8)。相反，FXR在淋巴谱系细胞中的表达尚未良好建立。通过蛋白质印迹分析(图8)，在H9细胞和活化的PBMC的全细胞裂解物中检测到FXR。在未活化的PBMC中检测不到或检测到非常微弱的条带。这种差异表明，PBMC活化诱导FXR表达或活化后CD4+T淋巴细胞的富集允许检测这些细胞中的FXR。
在没有FXR表达的情况下，FXR激动剂GW4064对HIV-1复制的影响被消除
使用shFXR慢病毒载体产生shFXR-H9细胞系。图9显示FXR确实在该细胞系中沉默。有趣的是，对照H9以及shFXR-H9细胞的处理进一步降低了FXR表达，表明FXR激活抑制其自身的表达。
在感染后第4天和第7天，与模拟处理的细胞相比，用HIV-1NL4.3和1μM的GW4064处理shCont-H9细胞再次导致p24和感染性病毒颗粒的早期产量增加(图10A、B和C)。病毒产量的这种早期增强随后是p24浓度和感染滴度在第9天强烈下降。GW4064处理对shFXR-H9细胞中的病毒产量没有影响，清楚地表明该分子的作用确实取决于FXR激活。有趣的是，GW4064似乎已经在1μM时达到了对感染性颗粒产量的最大影响。
FXR激动剂GW4064或6-ECDCA有助于重新激活潜伏性的原病毒
使用(2)中描述的Jurkat克隆8.4和15.4测试5μM的FXR激动剂GW4064和6-ECDCA对潜伏性感染细胞的影响。当用0.5μg/mL的TNFα处理细胞时，GFP+再活化细胞的百分比仅在两个克隆刺激后的第3天和第4天增加(图11A和B)。然而，15.4细胞的再活化百分比高于8.4。用任一种激动剂的共刺激诱导了在刺激后第1天已经可检测到的较高且较早的再活化。再活化与克隆15.4的细胞死亡率增加有关(图11C)。克隆8.4很难检测到这种影响(图11D)，可能是因为再活化细胞的比例太小而不能检测到这种影响，即使在共处理条件下活细胞的部分始终比TNFα处理细胞中略低。当用FXR激动剂共刺激细胞时，p24的产量也增加(图11E和F)。同样，克隆15.4比克隆8.4更具反应性。
FXR配体处理对BKV感染的原代人肾近端小管上皮细胞(RPTEC)的影响
然后测试FXR调节对BKV复制的影响，BKV是表达高水平FXR的原代人肾近端小管上皮细胞(RPTEC)中的多瘤病毒科的成员(数据未显示)。图12显示了处理3天和5天后FXR激动剂GW4064的作用结果。与模拟处理的细胞相比，观察到GW4064处理的细胞的上清液中产生的病毒滴度降低超过1.5个Log10。第5天的细胞计数表明在未感染的细胞中没有显著不同的细胞数，无论它们是否处理与否(分别为45200+/-10888对比59400+/-7660，p>0.13)。相反，感染细胞的数量显示，处理细胞的数量显著低于未处理细胞(分别为44800+/-7989对比74800+/-13163，p＝0.028)，表明FXR激动剂处理增加了感染培养物中的细胞死亡率(未显示)。
结论
令人惊讶地，我们发现FXR激动剂对不是专门用于胆汁盐代谢和转运的组织中的病毒复制具有活性。这一新发现清楚地表明，核受体FXR具有极大扩展代谢的功能。实际上，我们发现FXR激动剂处理对病毒的三个主要意外影响，其中病毒复制涉及病毒DNA基因组中间体。首先，FXR激动剂，但不是拮抗剂，实质上减少了两种典型病毒的复制，这两种典型病毒具有复制的DNA附加体中间体，病毒基因组整合或不整合到宿主细胞核染色质中，并且其依赖宿主机制进行病毒mRNA转录。实际上，就HIV-1而言，FXR激动剂的作用是双相的，其中病毒产量首先初始且瞬时增强，随后病毒复制急剧大幅下降。其次，另一个重要且令人惊讶的发现是由参与抗病毒活性的FXR活化诱导的感染细胞的高死亡率。并且第三，再次出乎意料地，FXR激动剂重新激活沉默的逆转录病毒整合的原病毒。细胞死亡率增加之后又重新激活。在FXR表达无效的细胞中缺乏任何作用证明了FXR在由FXR激动剂诱导的影响中的作用。
最重要的是，用两种具有非常不同的复制周期但共同存在DNA的附加体形式的病毒观察到这些影响，无论这些DNA基因组是否直接来自包含在循环病毒粒子中的基因组或通过基因组RNA的逆转录产生。因此，病毒转录受这些DNA中间体的调节，这些中间体可以整合或不整合到宿主细胞核染色质中。考虑到HBV(这是另一种依赖于复制的附加体中间体进行维持和转录的病毒)复制所观察到的影响，这些新发现表明，用配体进行FXR操作对于治疗共享这些性状的病毒的感染很有意义，即使在不涉及胆汁盐代谢的组织中。
重要的问题还有HIV-1潜伏性原病毒的再激活和由FXR激动剂处理诱导的细胞死亡。这些发现对HIV-1感染特别有意义，HIV-1感染的主要治疗目标不再是开发新的直接抗逆转录病毒药物(许多批准的直接作用的抗逆转录病毒药物是有效的病毒抑制剂)，而是清除以永久携带病毒基因组的细胞为特征的病毒库。因此，支持潜伏性原病毒再激活和感染细胞的死亡是降低受感染细胞库的重要工具。
与现有FXR激动剂相比，通过现有技术测定法测量的具有差的“激动剂”活性的其他FXR配体可以同样有效或更有效地抗病毒。基于针对HIV或具有附加体中间体的其他病毒的抗病毒活性的测定可用于筛选具有抗病毒活性的FXR配体。或者，激动剂可以在FXR的控制下诱导一些迄今未鉴定的基因的表达，所述基因可以参与染色体外DNA的清除。
因此，用FXR激动剂治疗的适应症扩展到大多数感染人类的DNA病毒，目的是抑制其复制并清除受感染的细胞库。
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Claims (10)
1.用于减少有需要的受试者的附加体病毒的持久性和表达的方法，包括向受试者施用治疗有效量的FXR激动剂。
2.根据权利要求1所述的方法，其中所述受试者是人或非人动物。
3.根据权利要求2所述的方法，其中所述受试者是家畜如猫和狗；牲畜和农场动物如马、牛、猪和鸡。
4.根据权利要求1所述的方法，其中所述附加体病毒选自属于腺病毒科、逆转录病毒科、疱疹病毒科、乳多空病毒科、多瘤病毒科、乳头瘤病毒科和细小病毒科的病毒。
5.根据权利要求1所述的方法，其中所述附加体病毒是腺病毒、疱疹病毒、乳头瘤病毒、多瘤病毒、细小病毒或逆转录病毒。
6.根据权利要求1所述的方法，其中所述附加体病毒选自下组：BKV、CMV、EBV、HHV8和HIV。
7.根据权利要求1所述的方法，其中所述受试者是免疫功能不全的，包括老年患者；AIDS患者；慢性免疫抑制治疗方案的患者，如器官移植患者；癌症患者，例如霍奇金病或淋巴瘤；以及患有自身免疫病症的患者，所述患者正在用替麦考酚酯或生物制剂如那他珠单抗、利妥昔单抗或依法珠单抗治疗，此类自身免疫病症包括但不限于多发性硬化症(MS)、类风湿性关节炎(RA)和系统性红斑狼疮(SLE)。
8.根据权利要求1所述的方法，其中所述受试者患有癌症并且施用细胞消融治疗，例如化疗或放疗。
9.根据权利要求1所述的方法，其中所述受试者是施用免疫抑制剂的移植受试者。
10.根据权利要求1所述的方法用于在高度活性的抗逆转录病毒治疗后根除HIV储库。
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| PCT/EP2018/058124 WO2018178260A1 (en) | 2017-03-30 | 2018-03-29 | Methods and pharmaceutical compositions for reducing persistence and expression of episomal viruses |
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| JP (1) | JP2020515564A (zh) |
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| JP2020515564A (ja) | 2020-05-28 |
| US20210085662A1 (en) | 2021-03-25 |
| EP3600293A1 (en) | 2020-02-05 |
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