CN114555089A - 用于乙型肝炎治疗的化合物 - Google Patents
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- CN114555089A CN114555089A CN202080070128.9A CN202080070128A CN114555089A CN 114555089 A CN114555089 A CN 114555089A CN 202080070128 A CN202080070128 A CN 202080070128A CN 114555089 A CN114555089 A CN 114555089A
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Abstract
本文描述了一种选自由AZ960、CYC116、MI‑3、Nexturastat A、TAK‑901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物,用于治疗乙型肝炎。所述化合物还可用于制造用于治疗乙型肝炎的药物。还描述了一种治疗受试者中的乙型肝炎感染的方法,所述方法包括向所述受试者施用治疗有效剂量的上述化合物。
Description
本发明涉及用于治疗乙型肝炎的新方法和化合物。
病毒性肝炎是由病毒感染引起的肝脏炎症。有五种会导致肝炎的主要肝炎病毒A-E。其中,乙型肝炎和丙型肝炎通常会导致患者中最严重的情况。当受感染的患者在感染后无法完全清除病毒时,乙型肝炎病毒(HBV)可引起急性和慢性肝炎。慢性肝炎可导致患者中的肝硬化或肝细胞癌(一种肝癌)。
尽管疫苗可用于预防甲型和乙型肝炎,并且是一种有效但昂贵的用于丙型肝炎的治疗,但由肝炎导致的全球死亡数呈上升趋势,如图1所示。相比之下,其他病毒性疾病,如HIV、疟疾和结核病(TB)呈明显下降趋势。世界卫生组织(WHO)制定了到2030年将乙型肝炎和丙型肝炎的新感染和死亡数分别减少90%和65%的目标。特别地,这可能是通过确定了乙型肝炎的功能性治愈,而护理标准的药物可用于丙型肝炎。
因此,需要用于肝炎特别是乙型肝炎的新治疗方法和药物。一种方法是制备新化合物并确定其对抗疾病的有效性。另一种方法是将现有化合物改变目的,包括未能从临床试验推进到市场上批准的药物的化合物。为现有药物寻找新的适应症特别有吸引力,因为潜在的副作用通常更为人所知,并为在现有药物添加新的适应症通常更容易获得监管部门的批准。这同样适用于可能由于单独或与标准护理批准的药物相比缺乏功效而尚未上市的化合物。
在本发明的一个方面,提供了一种选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物,用于治疗乙型肝炎。
在本发明的一个方面,提供了选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物在制造用于治疗乙型肝炎的药物中的用途。
上述抑制剂包括抑制剂的任何药学上可接受的盐形式和/或前药形式。Tubastatin A盐酸盐已经是一种盐,但可以使用其他药学上可接受的盐。
短语SEQ ID No.5至SEQ ID No.28是指SEQ ID No.5、SEQ ID No.6、SEQ ID No.7、SEQ ID No.8、SEQ ID No.9、SEQ ID No.10、SEQ ID No.11、SEQ ID No.12、SEQ ID No.13、SEQ ID No.14、SEQ ID No.15、SEQ ID No.16、SEQ ID No.17、SEQ ID No.18、SEQ IDNo.19、SEQ ID No.20、SEQ ID No.21、SEQ ID No.22、SEQ ID No.23、SEQ ID No.24、SEQ IDNo.25、SEQ ID No.26、SEQ ID No.27、和SEQ ID No.28。这类似地适用于本文使用的任何此类类似短语。
如picki and Gremecka(Future Med.Chem.2014,6(4),447-462)报道的,menin-MLL相互作用可能会被menin抑制剂破坏,因为menin与MLL1和MLL2二者结合并具有结构明确的蛋白质结合位点,结构刚性且在结合蛋白质配体时不会发生构象变化。因此,menin抑制剂可以充当menin-MLL抑制剂。
在上述两个方面,所述化合物可优选地选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
在本发明的另一个方面,提供了一种小干扰RNA分子,其包括SEQ ID No.5至SEQID No.28中的任一个。优选地,所述小干扰RNA分子用于治疗乙型肝炎或用于制造用于治疗乙型肝炎的药物。
在本发明的另一个方面,提供了一种治疗受试者中的乙型肝炎感染的方法,所述方法包括向所述受试者施用治疗有效剂量的选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物。
优选地,所述化合物选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
优选地,所述方法还包括施用具有抗乙型肝炎病毒活性的核苷类似物或聚乙二醇化干扰素。
优选地,核苷类似物选自由恩替卡韦、替诺福韦、拉米夫定、阿德福韦、替比夫定和化合物的任何前药和/或任何药学盐形式组成的组。聚乙二醇化干扰素可以是聚乙二醇化干扰素α-2a,或可以是聚乙二醇化干扰素α-2a、聚乙二醇化干扰素α-2b和聚乙二醇化干扰素β-1a。
在本发明的另一个方面,提供了一种组合物,其包含选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物,以及具有抗乙型肝炎病毒活性的核苷类似物或聚乙二醇化干扰素。聚乙二醇化干扰素可以是聚乙二醇化干扰素α-2a,或可以是聚乙二醇化干扰素α-2a、聚乙二醇化干扰素α-2b和聚乙二醇化干扰素β-1a。
优选地,所述化合物选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
优选地,所述核苷类似物选自由恩替卡韦、替诺福韦、拉米夫定、阿德福韦、替比夫定以及所述化合物的任何前药和/或任何药学盐形式组成的组。
在本发明的另一个方面,所述组合物用作药物。
优选地,所述组合物用于治疗乙型肝炎。
优选地,所述组合物用于制造用于治疗乙型肝炎的药物。
附图说明
图1示出了病毒性肝炎的负担和WHO 2030年减少肝炎感染和死亡数的目标;
图2示出了用于鉴定抗HBV的活性化合物(“HIT”)的方法;
图3示出了从表观遗传调节剂文库中鉴定的HIT化合物的抑制和细胞毒性结果;
图4示出了16种HIT化合物在HepG2 2.15细胞中的剂量反应曲线;
图5示出了6种选择的HIT及其治疗窗;
图6示出了用于培养HepAD38.7细胞(siRNA)的条件;
图7示出了HepAD38.7细胞中靶标功能性敲低抑制HBV的结果;
图8示出了原代人肝细胞中用于引入HBV感染的条件和药物处理方案;
图9表明HIT化合物降低了受感染的原代人肝细胞中的HBsAg;
图10表明HIT在受感染的原代人肝细胞中具有低细胞毒性
图11示出了用HIT化合物处理受感染的原代人肝细胞后的免疫荧光图像,图11a示出了在背景中用E-钙粘蛋白的感染对照中的HBcAg水平,图11b示出了第8天药物处理的细胞中的HBcAg水平,并且图11c示出了图11b中HBcAg强度的量化数据;
图12表明HIT化合物抑制原代人肝细胞中的eHBV和cccDNA水平;
图13示出了候选基因的RNAi敲低对白蛋白和pgRNA水平的影响;
图14表明候选基因的敲低抑制受感染的原代人肝细胞中的病毒,图14a和14b分别示出了通过qPCR测量的细胞外HBV DNA水平(在细胞培养上清液中)和cccDNA水平。
在以下描述中,阐述了许多具体细节以便提供对本发明的各种说明性实施方式的透彻理解。然而,本领域技术人员将理解,本发明的实施方式可以在没有这些具体细节中的一些或全部的情况下实施。在方法或设备之一的上下文中描述的实施方式类似地适用于其他方法或设备。类似地,在方法的上下文中描述的实施方式类似地适用于设备,反之亦然。
在一个实施方式的上下文中描述的特征可以相应地适用于其他实施方式中相同或相似的特征。在一个实施方式的上下文中描述的特征可以相应地适用于其他实施方式,即使在这些其他实施方式中没有明确描述。此外,在一个实施方式的上下文中针对特征描述的添加和/或组合和/或替代可以相应地适用于其他实施方式中的相同或相似特征。
术语“约”、“大约”、“基本上”必须参照整个申请的上下文来理解,并考虑到由该词限定的特定技术术语在相关领域中通常具有的含义。例如,可以理解,可以在一定的公差范围内执行或获得某个参数、功能、效果或结果,并且相关技术领域的技术人员知道如何获得该术语的公差。
短语“A和B中的至少一个”是指仅需要单独A、单独B、或A和B,即仅需要A或B之一。短语“A和/或B”包括单独A、单独B以及A和B。
出于说明书和权利要求的目的,本文使用的术语“药剂”和“药物”是指怀疑具有治疗特性的化合物、化合物的混合物、生物大分子或由生物材料如细菌、植物、真菌或动物(特别是哺乳动物)细胞或组织制成的提取物。药剂或药物可以是纯化的、基本纯化的或部分纯化的。
出于说明书和权利要求的目的,本文使用的术语“形态”是指细胞或生物体在用眼睛、光学显微镜、共焦显微镜或电子显微镜(视情况而定)观察时的视觉外观。
出于说明书和权利要求的目的,本文使用的术语“受试者”、“个体”和“患者”是指人或其他动物,例如农场动物或实验室动物(例如,豚鼠或小鼠),其具有细胞周期(受影响)确定的疾病,无论是自然发生的还是诱导的,包括但不限于癌症。
如本文所用,术语“协同作用”是指两种或更多种抗癌剂或化学治疗药物的组合作用可以大于单独的抗癌剂或化学治疗药物的单独作用的总和。
术语“治疗有效量”是指主题化合物的量,其将引起所需反应,例如,由例如研究人员、兽医、医生或其他临床医生寻求的组织、系统、动物或人的生物学或医学反应。
在整个说明书中,对特定化合物的任何叙述都应理解为包括该化合物、该化合物的前药及其任何(其他)药学上可接受的盐。术语“药学上可接受的盐”是指化合物的盐,该盐不会对施用它的生物体造成显著刺激并且不会消除该化合物的生物活性和性质。在一些实施方式中,盐是化合物的酸加成盐。药用盐可通过使化合物与无机酸诸如氢卤酸(例如盐酸或氢溴酸)、硫酸、硝酸、磷酸等反应来获得。药用盐也可以通过使化合物与有机酸反应获得,例如脂肪族或芳香族羧酸或磺酸,例如乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、烟酸、甲磺酸、乙磺酸、樟脑磺酸、对-甲苯磺酸、水杨酸或萘磺酸。药用盐也可以通过使化合物与碱反应来获得,以形成盐例如铵盐、碱金属盐例如钠盐或钾盐、碱土金属盐例如钙或镁盐、有机碱诸如二环己胺、N-甲基-D-葡糖胺、三(羟甲基)甲胺、C1-C7烷基胺、环己胺、三乙醇胺、乙二胺的盐,以及与氨基酸诸如精氨酸、赖氨酸等的盐。
如本文所用,多肽的“活性”或“生物活性”是指多肽的任何生物功能或任何生物相互作用。多肽的活性可以指多肽的酶活性或催化活性。多肽的活性也可以指多肽与细胞中的另一种多肽、多核苷酸或其他剂的结合。
如本文所用,“EC50”旨在指用于生物过程或过程的组分(包括蛋白质、亚基、细胞器、核糖核蛋白等)的50%激动或激活所需的物质(例如,化合物或药物)的浓度。在一个方面,EC50可以指50%的体内激动或激活所需的物质浓度,如本文别处进一步定义的。在另一个方面,EC50是指引起介于基线和最大反应之间一半处的反应的激动剂或激活剂的浓度。
如本文所用,“IC50”旨在指用于生物过程或过程的组分(包括蛋白质、亚基、细胞器、核糖核蛋白等)的50%抑制所需的物质(例如,化合物或药物)的浓度。例如,IC50可以指50%的体内抑制或体外测量抑制所需的物质浓度,如本文别处进一步定义的。或者,IC50是指物质的半数最大(50%)抑制浓度(IC)。抑制可以在细胞系例如AN3 CA、BT-20、BT-549、HCT 116、HER218、MCF7、MDA-MB-231、MDA-MB-235、MDA-MB-435S、MDA-MB-468、PANC-1、PC-3、SK-N-MC、T-47D和U-87MG中测量。在又一个方面,抑制在用突变型或野生型哺乳动物组蛋白脱甲基酶例如LSD1或LSD2转染的细胞系例如HEK-293或HeLa中测量
术语“类似物”是指不相同但具有类似功能或结构特征的分子。例如,核苷类似物模拟核苷活性,但核苷部分或糖部分结构不同。实例包括脱氧腺苷和腺苷类似物、脱氧胞苷类似物、鸟苷和脱氧鸟苷类似物、胸苷和脱氧胸苷类似物以及脱氧尿苷类似物。例如,多肽类似物保留了相应天然存在的多肽的生物活性,同时具有某些生化修饰,其相对于天然存在的多肽增强了类似物的功能。这样的生化修饰可以增加类似物的蛋白酶抗性、膜通透性或半衰期,而不会改变配体结合等。类似物可以是具有至少一个与天然存在的多肽不同的氨基酸的多肽,并且可以包括非天然氨基酸。
如本文所用,术语“受试者”是指作为施用目标的活生物体。本文公开的方法的受试者可以是脊椎动物,例如哺乳动物、鱼、鸟、爬行动物或两栖动物。因此,本文公开的方法的受试者可以是人类、非人类灵长类动物、马、猪、兔、狗、绵羊、山羊、牛、猫、豚鼠或啮齿动物。该术语不表示特定的年龄或性别。因此,旨在涵盖成年和新生儿受试者以及胎儿,无论是雄性还是雌性。患者是指患有疾病或病患的受试者。术语“患者”包括人类和兽医受试者。
如本文所用,术语“预防”或“防止”是指排除、避免、消除、阻止、停止或阻碍某事发生,尤其是通过提前行动。应当理解,在本文中使用减少、抑制或防止的情况下,除非另有明确说明,其他两个词的使用也被明确公开。在某些方面,该术语可以与语言“预防性治疗”同义。
如本文所用,术语“缓解”或“减轻”是指降低或减轻症状、病症或病患的严重性。例如,减轻受试者疼痛严重程度的治疗可以说是缓解疼痛。应当理解,在某些情况下,治疗可以缓解症状或病症而不治疗潜在病患。在某些方面,该术语可以与语言“姑息治疗”同义。
如本文所用,术语“施用”和“给药”是指向受试者提供药物制剂的任何方法这样的方法为本领域技术人员所熟知,并且包括但不限于口服施用、透皮施用、吸入施用、鼻腔施用、局部施用、阴道内施用、眼部施用、耳内施用、脑内施用、直肠施用和肠胃外施用,包括可注射剂,例如静脉内施用、动脉内施用、肌肉内施用和皮下施用。施用可以是连续的或间歇的。在多个方面,制剂可以治疗性地施用;即,用于治疗现有疾病或病症。在另外多个方面,制剂可以预防性地施用;即,施用以预防疾病或病症。在一个方面,片剂的施用是指口服施用。
在另一个方面,本发明涉及一种药物组合物,其包含生理上可接受的表面活性剂、载体、稀释剂、赋形剂、平滑剂、悬浮剂、成膜物质和包衣助剂或其组合;以及本文公开的化合物。药物组合物有助于将化合物施用于生物体。用于治疗用途的可接受的载体或稀释剂在制药领域是众所周知的,并且描述在例如Remington's Pharmaceutical Sciences,18thEd.,Mack Publishing Co.,Easton,PA(1990)中,其通过引用整体并入本文。药物组合物中可以提供防腐剂、稳定剂、染料、甜味剂、香料、矫味剂等。例如,可以添加苯甲酸钠、抗坏血酸和对羟基苯甲酸酯作为防腐剂。此外,可以使用抗氧化剂和助悬剂。在各种实施方式中,醇、酯、硫酸化脂肪醇等可用作表面活性剂;蔗糖、葡萄糖、乳糖、淀粉、结晶纤维素、甘露醇、轻质无水硅酸盐、铝酸镁、偏硅酸铝酸镁、合成硅酸铝、碳酸钙、酸式碳酸钠、磷酸氢钙、羧甲基纤维素钙等可用作赋形剂;硬脂酸镁、滑石、硬化油等可用作平滑剂;椰子油、橄榄油、芝麻油、花生油、大豆可用作悬浮剂或润滑剂;作为碳水化合物如纤维素或糖的衍生物的乙酸邻苯二甲酸纤维素,或作为聚乙烯基的衍生物的乙酸甲酯-甲基丙烯酸酯共聚物可用作悬浮剂;并且增塑剂如邻苯二甲酸酯等可用作悬浮剂。
可以将另外的治疗剂或诊断剂引入药物组合物中。替代地或另外地,药物组合物可与含有其他治疗剂或诊断剂的其他组合物组合。
应当理解,本文提供的组合物可以是允许将组合物施用于患者的任何形式。例如,组合物可以是固体、液体或气体(例如气溶胶)的形式。合适的施用途径包括但不限于肠内(例如口服或直肠)、局部、肠胃外(例如舌下、口腔、舌下、阴道或鼻内)。如本文所用的术语肠胃外包括皮下注射、静脉内、动脉内、皮内、肌肉内、胸骨内、海绵体内、鞘内、腹腔内、眼内注射或输注技术。药物组合物被配制为使得其中所含的活性成分在将组合物施用于患者时是生物可利用的。待施用于患者的组合物采取一个或多个剂量单位的形式,其中例如片剂可以是单一剂量单位,并且气溶胶形式的一种或多种本发明化合物的容器可以容纳多个剂量单位。化合物还可以以持续释放或受控释放剂型施用,包括储库注射剂、渗透泵、丸剂、透皮(包括电转运)贴剂等,用于以预定速率延长和/或定时、脉冲施用。
可以单独调整剂量和间隔以提供足以维持调节作用或最小有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC会有所不同,但可以根据体外数据进行估算。达到MEC所需的剂量将取决于个体特征和施用途径。然而,HPLC测定或生物测定可用于确定血浆浓度。通常,剂量可以在约10微克/kg和100mg/kg体重之间,优选地在约100微克/kg和10mg/kg体重之间。或者,如本领域技术人员所理解的,剂量可以基于患者的表面积计算。
应当注意,主治医师会知道由于毒性或器官功能障碍如何以及何时终止、中断或调整施用。相反,如果临床反应不充分,主治医师也会知道将治疗调整到更高的水平(排除毒性)。治疗目标病患的施用剂量的大小将随着待治疗的病症的严重程度和施用途径而变化。例如,可以部分地通过标准预后评估方法来评估病症的严重性。此外,剂量和可能的剂量频率也将根据个体患者的年龄、体重和反应而变化。与上面讨论的程序相当的程序可用于兽医学。
虽然确切的剂量将在逐个药物的基础上确定,但在大多数情况下,可以对剂量进行一些概括。成人患者的每日给药方案可以是,例如,口服剂量为每种活性成分在每天0.1mg/m2和2000mg/m2体表面积之间,通常在每天1mg/m2和500mg/m2体表面积之间,例如每天5mg/m2至200mg/m2体表面积。在其他实施方式中,可以使用每天0.01mg/m2和100mg/m2体表面积之间,通常每天0.1/m2 mg和60mg/m2体表面积之间,例如每天1mg/m2至40mg/m2体表面积的每种活性成分的静脉内、皮下或肌肉内剂量。在施用药学上可接受的盐的情况下,剂量可以以游离碱计算。在一些实施方式中,组合物每天施用1至4次。替代地,本发明的组合物可以通过连续静脉内输注施用,优选每种活性成分的剂量最高至每天1000mg/m2体表面积。
如本领域技术人员将理解的,在某些情况下,可能需要以超过或甚至远超过上述优选剂量范围的量施用本文公开的化合物,以便有效和积极地治疗特别是侵袭性的疾病或感染。在一些实施方式中,将化合物施用持续治疗期,例如一周或更长时间,或数月或数年。
剂量间隔也可以使用MEC值来确定。组合物应使用在10-90%的时间内,通常在30-90%和最通常在50-90%的时间内维持高于MEC的血浆水平的方案来施用。在局部施用或选择性摄取的情况下,药物的有效局部浓度可能与血浆浓度无关。
本发明的药物组合物可以以本身已知的方式制造,例如,通过常规的混合、溶解、制粒、糖衣丸制造、研磨、乳化、包封、包埋或压片工艺。
可以使用已知方法评估本文公开的化合物的功效和毒性。例如,共有某些化学部分的特定化合物或化合物子集的毒理学可以通过测定对细胞系如哺乳动物,优选人类细胞系的体外毒性来确定。这些研究的结果通常可以预测在动物,例如哺乳动物,或者更特别地人类中的的毒性。替代地,可以使用已知方法确定中特定化合物在动物模型例如小鼠、大鼠、兔或猴中的毒性。可以使用多种公认的方法例如体外方法、动物模型或人体临床试验来确定特定化合物的功效。对于几乎所有类型的病症,包括但不限于癌症、心血管疾病和各种免疫功能障碍都存在公认的体外模型。类似地,可接受的动物模型可用于确定化学品治疗这样的病症的功效。在选择模型以确定功效时,本领域技术人员可以在现有技术的指导下选择合适的模型、剂量和施用途径以及方案。当然,人体临床试验也可用于确定化合物在人类中的功效。
特定药物制剂
可将可注射剂制备成常规形式,作为液体溶液或混悬剂、适合在注射前溶解或悬浮在液体中的固体形式,或作为乳剂。合适的赋形剂是例如水、盐水、右旋糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、半胱氨酸盐酸盐等。此外,如果需要,可注射药物组合物可包含少量无毒辅助物质,例如润湿剂、pH缓冲剂等。生理相容的缓冲液包括但不限于汉克斯溶液、林格溶液或生理盐水缓冲液。如果需要,可以使用吸收增强制剂(例如,脂质体)。
对于经粘膜施用,适合于待渗透屏障的渗透剂可用于制剂中。用于肠胃外施用的药物制剂(例如通过推注或连续输注)包括水溶性形式的活性化合物的水溶液。此外,活性化合物的混悬剂可以制备成合适的油性注射混悬剂。合适的亲脂性溶剂或载剂包括脂肪油,例如芝麻油,或其他有机油,例如大豆、葡萄柚或杏仁油,或合成脂肪酸酯,例如油酸乙酯或甘油三酯,或脂质体。水性注射混悬剂可能含有增加混悬剂粘度的物质,例如羧甲基纤维素钠、山梨糖醇或葡聚糖。任选地,混悬剂还可以含有合适的稳定剂或增加化合物溶解度的试剂以允许制备高度浓缩的溶液。注射用制剂可以以单位剂型存在,例如,在安瓿或多剂量容器中,并添加防腐剂。组合物可以采取诸如在油性或水性载剂中的混悬剂、溶液剂或乳剂的形式,并且可以包含配制剂,例如助悬剂、稳定剂和/或分散剂。或者,活性成分可以是粉末形式,用于在使用前用合适的载剂例如无菌无热原水混合。对于口服施用,可以通过将活性化合物与本领域熟知的药学上可接受的载体组合来容易地配制化合物。这样的载体能够将本发明的化合物配制成片剂、丸剂、糖衣丸、胶囊、液体、凝胶、糖浆、浆液、混悬剂等,以供待治疗的患者口服摄取。口服药物制剂可通过将活性化合物与固体赋形剂组合,任选研磨所得混合物,并且如果需要,在添加合适的助剂后加工颗粒混合物以获得片剂或糖衣丸芯来获得。合适的赋形剂尤其是填充剂,例如糖,包括乳糖、蔗糖、甘露糖醇或山梨糖醇;纤维素制剂,例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮(PVP)。如果需要,可以添加崩解剂,例如交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐例如海藻酸钠。糖衣丸芯配有合适的涂层。为此目的,可以使用浓缩糖溶液,其可以任选地含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。可以将染料或颜料添加到片剂或糖衣丸包衣中以用于识别或表征活性化合物剂量的不同组合。为此目的,可以使用浓缩糖溶液,其可以任选地含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。
可口服使用的药物制剂包括由明胶制成的推入配合胶囊(push-fit capsule),以及由明胶和增塑剂(例如甘油或山梨糖醇)制成的软密封胶囊。推入配合胶囊可包含与填充剂如乳糖、粘合剂诸如淀粉和/或润滑剂诸如滑石或硬脂酸镁和任选的稳定剂混合的活性成分。在软胶囊中,活性化合物可以溶解或悬浮在合适的液体例如脂肪油、液体石蜡或液体聚乙二醇中。此外,可以添加稳定剂。所有用于口服施用的制剂都应采用适合这种施用的剂量。对于口腔施用,组合物可以采用以常规方式配制的片剂或锭剂的形式。
对于吸入施用,根据本发明使用的化合物方便地以气溶胶喷雾形式从加压包装或喷雾器中递送,其使用合适的抛射剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体。在加压气溶胶的情况下,剂量单位可以通过提供递送计量的量的阀门来确定。可配制用于吸入器或吹入器的例如明胶的胶囊和药筒,其包含化合物和合适的粉末基质诸如乳糖或淀粉的粉末混合物。
化合物还可以配制成直肠组合物,例如栓剂或保留灌肠剂,其例如包含常规栓剂基质诸如可可脂或其他甘油酯。
除了前面描述的制剂,这些化合物也可以配制成储库制剂。这种长效制剂可以通过植入(例如皮下或肌肉内)或通过肌肉内注射来施用。因此,例如,化合物可以与合适的聚合或疏水材料(例如作为可接受油中的乳剂)或离子交换树脂一起,或作为微溶衍生物,例如作为微溶盐配制。对于疏水性化合物,合适的药物载体可以是包含苯甲醇、非极性表面活性剂、水混溶性有机聚合物和水相的助溶剂系统。常用的助溶剂系统是VPD助溶剂系统,它是由3%w/v苯甲醇、8%w/v非极性表面活性剂Polysorbate 80TM和65%w/v聚乙二醇300在无水乙醇中补足至体积的溶液。自然地,助溶剂系统的比例可以有很大的变化,而不会破坏其溶解度和毒性特征。此外,助溶剂成分的种类可能会有所不同:例如,可以使用其他低毒性非极性表面活性剂代替POLYSORBATE 80TM;聚乙二醇的级分大小可以变化;其他生物相容性聚合物可以替代聚乙二醇,例如聚乙烯吡咯烷酮;并且其他糖或多糖可以替代葡萄糖。
替代地,可以使用用于疏水药物化合物的其他递送系统。脂质体和乳剂是用于疏水药物的递送载剂或载体的众所周知的实例。也可以使用某些有机溶剂,例如二甲亚砜,尽管通常以更大的毒性为代价。此外,可以使用缓释系统递送化合物,例如含有治疗剂的固体疏水聚合物的半透性基质。已经建立了多种缓释材料并且为本领域技术人员所熟知。根据其化学性质,缓释胶囊可能会释放化合物数周最高达超过100天。根据治疗试剂的化学性质和生物稳定性,可以采用额外的蛋白质稳定策略。
如果需要,组合物可以装在包装或分配装置中,该包装或分配装置可以包含一种或多种含有活性成分的单位剂型。该包装可以例如包括金属或塑料箔,例如泡罩包装。包装或分配装置可以附有施用说明。包装或分配器还可以附有与容器相关的通知,其形式由管理药品制造、使用或销售的政府机构规定,该通知反映了该机构对用于人或兽医施用的药物形式的批准。例如,这样的通知可能是美国食品和药物管理局批准的处方药标签,或批准的产品说明书。还可以制备包含配制在相容药用载体中的本发明化合物的组合物,放置在适当的容器中,并贴上标签用于治疗指定的病症。
如本文所用,术语“施用”和“给药”是指向受试者提供药物制剂的任何方法这样的方法为本领域技术人员所熟知,并且包括但不限于口服施用、透皮施用、吸入施用、鼻腔施用、局部施用、阴道内施用、眼部施用、耳内施用、脑内施用、直肠施用和肠胃外施用,包括注射剂,例如静脉内施用、动脉内施用、肌肉内施用和皮下施用。施用可以是连续的或间歇的。在多个方面,制剂可以治疗性地施用;即,用于治疗现有疾病或病症。在另外多个方面,制剂可以预防性地施用;即,施用以预防疾病或病症。在一个方面,片剂的施用是指口服施用。
如本文所用,术语“立即释放”是指指示期望物质相对立即地释放到其目标环境的属性。在一个方面,“立即释放”片剂在施用后小时内释放超过约40%的期望物质,如在片剂溶出度测试(Tablet Dissolution Test)下测量的。
如本文所用,术语“受控释放”是指指示期望物质如药物(例如镁盐)以受控方式而不是立即释放到其目标环境(例如受试者)的属性。因此,“受控释放”制剂在施用后1小时内释放不超过约40%的期望物质,如在片剂溶出度测试下测量的。“受控释放”包括“延迟释放”和“持续释放”制剂二者。在一个方面,“受控释放”不包括“立即释放”制剂;然而,预期某些“受控释放”制剂可以包括立即释放方面。例如,具有立即释放控制核心和肠溶衣的制剂不会被称为“立即释放”制剂;这样的制剂可以称为“受控释放”制剂和“延迟释放”制剂,但不能称为“持续释放”制剂。“受控释放”片剂的实例包括“延迟释放”片剂、“持续释放”片剂和“延迟/持续释放”片剂。
如本文所用,术语“延迟释放”是指指示期望物质例如药物(例如镁盐)在施用后并非立即的时间释放到其目标环境(例如受试者)的属性。在一个方面,剂型控制药物释放到胃肠道中的速率,在十二指肠远侧的胃肠道的一部分中释放大部分药物。这可以降低胃肠道副作用的发生率或严重程度。此外,这可以增加吸收到血液中的药物量。在另一个方面,“延迟释放”制剂在施用后2小时内释放不超过约5%的期望物质。在又一个方面,“延迟释放”制剂在施用后2小时内释放不超过约5%的期望物质,并在施用后3小时内释放不超过约40%的期望物质。在更进一步的方面,“延迟释放”制剂在施用后2小时内释放不超过约5%的期望物质,在施用后3小时内释放不超过约40%的期望物质,并且在施用后8小时内释放不超过约80%的期望物质。在更进一步的方面,“延迟释放”制剂在施用后2小时内释放不超过约5%的期望物质,在施用后4小时内释放不超过约40%的期望物质,并且在施用后8小时内释放约50至约80%的期望物质。在另一个方面,基本上全部药物在12小时内释放。“延迟释放”是“受控释放”的一个子集。FDA指南还将“延迟释放”片剂称为固体剂型,其在施用后并非立即的时间释放药物(或多种药物)。肠溶衣制品是延迟释放剂型。该术语包括“延迟释放”片剂和“延迟/持续释放”片剂二者。
如本文所用,术语“持续释放”是指指示期望物质如药物(例如镁盐)以期望剂量释放到其目标环境(例如受试者)的属性,该期望剂量在期望间隔内维持。在一个方面,该属性也可以称为“延时释放”或“延长释放”。在一个方面,剂型控制药物释放速率以降低给药频率。这可以保持药物的期望血液水平,而不依赖于给药频率。这也可以增加患者对给定治疗方案的依从性。在另一个方面,剂型控制药物释放速率以靶向远侧小肠。在又一个方面,剂型控制药物释放速率以靶向远侧小肠,从而增加可用于与TRPM6和/或TRPM7阳离子通道相互作用的镁量。在另一个方面,“持续释放”制剂在施用后1小时内释放不超过约40%的期望物质。在又一个方面,“持续释放”制剂在施用后1小时内释放不超过约40%的期望物质,并在施用后6小时内释放不超过约80%的期望物质。在甚至又一个方面,“持续释放”制剂在施用后1小时内释放不超过约40%的期望物质,并在施用后6小时内释放约50至约约80%的期望物质。在另一个方面,基本上全部药物在10小时内释放。在又一个方面,“持续释放”制剂在施用后2小时内释放不超过约5%的期望物质,并在施用后3小时内释放不超过约40%的期望物质。在甚至又一个方面,“持续释放”制剂在施用后2小时内释放不超过约5%的期望物质,在施用后3小时内释放不超过约40%的期望物质,并且在施用后8小时内释放不超过约80%的期望物质。在甚至又一个方面,“持续释放”制剂在施用后2小时内释放不超过约5%的期望物质,在施用后3小时内释放不超过约40%的期望物质,并且在施用后8小时内释放约50%至约80%的期望物质。在另一个方面,基本上全部的整个药物在12小时内释放。“持续释放”是“受控释放”的一个子集。FDA指南还将“持续释放”片剂称为“延时释放片剂”——即含有药物的固体剂型,与常规剂型中的存在的药物相比,其至少使得给药频率减少。该术语包括“持续释放”片剂和“延迟/持续释放”片剂二者。
材料和方法
细胞培养和治疗:
本研究中使用的HepAD38.7-Tet细胞在补充有1%Pen Strep、10%无四环素的FBS(Biowest)、400μg/mL G418和/或5μg/mL四环素的HyClone DMEM培养基中培养。PHH购自BioreclamationIVT(产品编号:UNR-M00995-P),并根据BioIVT方案进行回收。将细胞维持在含有B27、Glutamax(Gibco)和Pen Strep(Gibco)的Williams培养基E中,并补充5C条件:20μM毛喉素、10μM B431542、0.5μM IWP2、5μM DAPT和0.1μMLDN193189,如所述。
寡核苷酸,siRNA。本研究中使用的寡核苷酸是使用Primer Plus设计的,并由Integrated DNA technologies,Inc(IDT)合成。从Silencer Select(AppliedBiosystems)订购了针对69个基因的3个不同区域的经过验证的siRNA。
PHH的HBV感染。如前所述,在存在4%PEG8000和1%DMSO的情况下,以200的200个基因组当量感染原代人肝细胞。在图例中指定的时间点收获样品、用于RNA和/或DNA的细胞裂解物以及细胞培养上清液。
HepAD38.7细胞中的RNAi筛选。如前所述维持HepAD38.7细胞。以20nM的最终浓度在384孔板中对每个基因的三个siRNA的文库进行点样。根据LipofectamineTM 3000试剂方案(Opti-MEM培养基中每孔0.1μL Lipofectamine 3000)(ThermoScientific),通过反向转染进行基因沉默。洗涤细胞,并在转染后一天更换培养基。将转染的细胞在37℃、5%CO2的培养箱中孵育72小时。为了重现性,筛选独立重复3次。板中包含四个技术重复,并且每次筛选包含2个生物重复。孵育三天后,收获细胞培养上清液用于HBsAg ELISA。为了收获足够的样品用于RNA、DNA提取和ELISA,以24孔和12孔的放大形式进行了后续筛选。
HBsAg ELISA。如下文详细描述进行HBsAg ELISA。简而言之,在图例所示的时间点收集25μL细胞培养上清液并用于HBsAg ELISA。
试剂:
链霉亲和素-HRP Elisa 1ml,Cat#(421)554066–BD Bioscience/Zuellig Pharma
TMB Substrate OptEIA Reagent Set,Cat#(421)555214–BD Bioscience/Zuellig Pharma
CAP碳酸盐-碳酸氢盐缓冲液胶囊,Cat#C3041-100–TR Sigma Aldrich
384孔聚苯乙烯板maxisorp,透明,Cat#P6366-1CS-Sigma Aldrich
乙型肝炎病毒表面抗原(Ad/Ay)的小鼠单克隆[86c],Cat#ab20758–Abcam
乙型肝炎病毒表面抗原(Ad/Ay)的兔多克隆(生物素),Cat#ab68520–Abcam
活性乙型肝炎表面抗原(Adw)全长蛋白,Cat#ab91276–Abcam
Tween 20
洗涤缓冲液:0.05%Tween 20在1x PBS中
测定稀释剂:10%FBS在1x PBS中
程序
1.用在包被缓冲液(6ug/ml;300ul来自10ml包被缓冲液中的0.2mg/ml原液)中稀释的小鼠单克隆[86C]以每孔25ul包被微孔(150ng/孔)。
2.将板密封并在4℃下孵育过夜。
3.抽吸孔并用50ul/孔的洗涤缓冲液洗涤3次。
4.最后一次洗涤后,将板倒置并在c-towel上吸干,并以1000rpm旋转1分钟以去除残留溶液。
5.用75ul/孔的测定稀释剂封闭板。在室温下孵育2小时。
6.如步骤3中所述抽吸/洗涤。
7.在测定稀释剂中制备4000ng/ml活性HBS Ag(Adw)全长蛋白,并针对12个不同的2倍递减浓度滴定。吸取25ul样品和不同稀释度的活性HepB表面Ag(Adw)到适当的孔中。将板密封并在室温下孵育2小时。
8.如步骤3中所述抽吸/洗涤,但总共洗涤5次。
9.向每个孔中加入25ul工作检测物(兔多克隆HBS-Biotin(4500ng/ml)+SAv-HRP(1:1000)试剂。将板密封并在室温下孵育1小时。
10.如步骤3中所述抽吸/洗涤,但洗涤7次。
11.向每个孔中加入25ul TMB底物溶液,并将板在室温避光孵育30分钟。
12.每孔加入25ul终止溶液(1N HCl),终止反应后30分钟内在450nm处读取吸光度。
定量实时PCR。根据Total RNeasy试剂盒方案(Qiagen)从细胞裂解物中提取RNA。在Quantstudio 7PCR系统(Applied Biosystems)中使用基于SYBR Fast的RT-PCR试剂盒检测前基因组RNA。
使用的pgRNA引物:
正向:CGTTTTTGCCTTCTGACTTCTTTC(SEQ ID No.1)以及
反向:ACAGAGCTGAGGCGGTGTCTA(SEQ ID No.2)。
如图例中所示,从实验结束时收集的200μL细胞培养上清液中提取HBV细胞外DNA。根据QIAamp DNA Mini Kit(Qiagen)提取DNA。
用于检测细胞外DNA的HBV DNA引物:
正向:CCGTCTGTGCCTTCTCATCTG(SEQ ID No.3)以及
反向:AGTCCAAGAGTCCTCTTATGTAAGACCTT(SEQ ID No.4)。
本研究中用于定量聚合酶链式反应(qPCR)的所有引物均购自Integrated DNATechnologies。如所述,使用Livack方法分析qPCR数据。
蛋白质印迹分析。在实验结束时,在补充有1X蛋白酶和磷酸酶抑制剂混合物(Roche)的放射免疫沉淀测定(RIPA)缓冲液(Cat No:89900,ThermoScientific)中收获细胞。裂解物进一步在冰上孵育30分钟,然后在4℃下以14,000Xg离心15分钟使其澄清。收获上清液,并根据制造商的方案通过二辛可宁酸蛋白质测定法(ThermoScientific,cat no:23225)对蛋白质进行定量。将30μg蛋白质在95℃下煮沸5分钟,然后通过SDS-聚丙烯酰胺凝胶电泳分离。然后将分离的蛋白质转移到PVDF膜上,用InterceptTM(TBS)缓冲液(Bio-Rad,P/N:927-70001)或5%脱脂牛奶在室温下封闭1小时,并在4℃下与一抗一起孵育过夜。将膜用1X TBST洗涤3次,并与LI-COR800CW或680CW抗体在室温下孵育1小时。将膜用1X TBST洗涤5次,并使用ChemiDoc XRS+系统(Bio-Rad)进行可视化。
统计分析。在GraphPad prism 8中使用图例中所示的不同测试进行数据分析。如所述,在STRING数据库上进行上调基因的网络分析。如报道的,在R studio中使用DEGseq包分析来自RNAseq数据的差异表达基因。
图2示出了鉴定用于治疗乙型肝炎的命中的(hit)化合物并开发成用于治疗乙型肝炎的可能候选物的工作流程或方法200。特别地,其示出了表观遗传调节剂的高通量筛选,基于高HBsAg降低和低细胞毒性确定HIT,在HepAD8.7(用于HBV复制的表达系统)和活感染模型(HepG2-NTCP细胞系和原代人肝细胞)中验证。在方框205中,在HepG2 2.15细胞中对化合物文库进行初级筛选,以确定BsAg(乙型肝炎病毒的表面抗原,表明患者中的乙型肝炎感染)的抑制活性和平行的细胞毒性。在方框310中,通过鉴定具有特定标准的化合物来确定命中的化合物(“HITS”或“HITs”)。例如,活性大于50%(即大于50%抑制),以及任选具有小于20%细胞毒性或约20%细胞毒性的化合物。在初级筛选中,通常以比预期更高的浓度测试化合物,并可能导致超出预期的细胞毒性(>20%)。例如,可以在3μM(本文示出的数据)或10μM下测试化合物。然而,该化合物随后以适当的剂量反应方式(如下所述)进一步测试,以确定该药物是否能够引起具有低细胞毒性(即<20%细胞毒性)的抗病毒反应(降低HBsAg水平)。
在方框215中,进行二级筛选以确定HIT化合物的EC50值(获得50%活性或抑制的有效浓度)。在方框220中,在HEPAD38.7 HBV活感染模型中测试命中的化合物以确定命中的化合物的鲁棒性,即命中的化合物是否有效。在方框225中,鉴定了新的先导化合物或骨架结构,并开发了用于靶标接合的作用机制(MOA)研究。在方框230中,优化和验证先导化合物,或者如果该化合物是已知的但用于不同的非生物用途或生物靶标,则该化合物可以改变目的用于抑制HBV。在方框235中,在动物模型中确定了化合物的功效。
初级筛选中使用了化合物文库。该文库包含以下酶的抑制剂:组蛋白脱乙酰化酶(HDAC)、sirtuins(SIRT)、组蛋白甲基转移酶(HMT)、DNA甲基转移酶以及SIRT激活剂。抑制剂具有多种结构和机制不同的化合物类别。
该文库可以由来自Enzo的包含42种化合物的市售文库和来自Selleckchem的包含151种化合物的市售文库组成。这些化合物对进行表观遗传修饰的酶具有已知的活性(如上所述)。这些文库是用于化学基因组学、分析开发和其他药理学应用的有用工具。
此外,该文库还可以包含Micro Source–Spectrum集合,它是生物活性化合物和天然产物的集合,包含约2400种化合物,并且包括美国和国际药物集合(US andInternational Drug Collections)以及MicroSource Natural Product and Discover文库中的所有化合物。
从SelleckChem化合物文库中的3μM浓度的151种表观遗传调节剂的初级高通量筛选中,鉴定出16种命中的化合物具有良好的抗病毒活性,导致高HBsAg损失(>50%)和低细胞毒性(<20%)并且结果如图3所示。高通量筛选的命中率约为10%。
下面的表1示出了鉴定的命中的化合物、它们已知的抑制活性和化学结构。
表1:HIT化合物
对命中的化合物进行二级筛选以确定命中的化合物的EC50。图4示出了化合物在HepG2 2.15细胞中从30μM开始的8点剂量反应曲线。浅色曲线或线(上曲线)示出了%HBsAg抑制,而深色曲线或线(下曲线)示出了细胞毒性。所有16种化合物均显示出HBsAg抑制。然而,可以观察到只有AZ960、CYC116、MI-3、TAK-901、Tubastatin A盐酸盐和Nexturastat A显示出合适的剂量反应曲线(即%抑制随剂量变化)。其他一些化合物被确定为不太合适。例如,alisertib在降低HBsAg水平方面没有那么有效,也没有显示对HepAD38细胞的影响。MI-2的EC50非常高并且似乎取决于化合物的毒性,因此不是可行的选择。图4中MC1568、OF-1和托法替尼的百分比抑制曲线在纵轴上接近于0,在图4中可能不容易看出。可以看出,二级筛选能够从一级筛选中过滤掉不合适的化合物。
在图5中,示出了六种最有希望的化合物——AZ960、CYC116、MI-3、TAK-901、Tubastatin A盐酸盐和Nexturastat A的治疗窗。治疗窗定义为化合物的EC50与达到50%细胞毒性之间的化合物浓度。表2提供了这6种化合物的HBsAg抑制和细胞毒性的IC50值,并以数字形式示出了治疗窗。两种化合物是极光激酶抑制剂(TAK-901和CYC-116),两种化合物是HDAC6抑制剂(Nexturastat A和Tubastatin A HCl),一种化合物是已知的Menin-MLL相互作用抑制剂(MI-3)并且最后一种是JAK-2的抑制剂(AZ960)。
表2:在Hep G2 2.15细胞中HBsAg抑制和细胞毒性的IC50值
基于这六种化合物,根据之前注释的靶标——JAK2、极光激酶A和B(AURKA和AURKB)、Menin-MLL相互作用和HDAC6,确定了可能的机制目标。设计针对这些中的每一种的siRNA以探测它们对HBV的影响。
还使用Lipofectamine 3000试剂对HepAD38.7细胞中的药物筛选和功能基因敲低进行了二次验证。所选基因是所选表观遗传抑制剂的注释靶标。
图6示出了培养HepAD38.7细胞和用小干扰RNA(siRNA)处理的实验装置。在该方法中使用四环素依赖性病毒诱导。HBV保持在“病毒开启”状态,并与细胞一起接种在24孔板中。第二天,各自添加不同的siRNA(序列见表3),包括siAURKA、siAURKB、siMenin1、siHDAC6、siJAK2,以及siRNA阴性对照。3天后,收集上清液用于HBsAg ELISA测定以及DNA分离用于eHBV分析。
将细胞固定在4%多聚甲醛中并用0.2%Trition X 100透化并用HBcAg抗体染色以通过IFA确定抗原水平。
从细胞裂解物中分离DNA,使用质粒安全的ATP依赖性DNA酶进行纯化以去除非环状DNA(松弛环状DNA)。然后使用基于Taqman探针的定量聚合酶链式反应测量cccDNA水平。
表3:Silencer select人siRNA序列用于HepAD38.7细胞和原代人肝细胞二者中的功能性敲低
AURKA
AURKB
HDAC6
MEN1
SEQ ID No.5:AURKA siRNA A序列S:GCGCAUUCCUUUGCAAGCATT
SEQ ID No.6:AURKA siRNA A序列A/S:UGCUUGCAAAGGAAUGCGCTG
SEQ ID No.7:AURKA siRNA B序列S:GAGUCUACCUAAUUCUGGATT
SEQ ID No.8:AURKA siRNA B序列A/S:UCCAGAAUUAGGUAGACUCTG
SEQ ID No.9:AURKA siRNA C序列S:GGAUCAGCUGGAGAGCUUATT
SEQ ID No.10:AURKA siRNA C序列A/S:UAAGCUCUCCAGCUGAUCCAA
SEQ ID No.11:AURKB siRNA A序列S:CCUGCGUCUCUACAACUAUTT
SEQ ID No.12:AURKB siRNA A序列A/S:AUAGUUGUAGAGACGCAGGAT
SEQ ID No.13:AURKB siRNA B序列S:UCGUCAAGGUGGACCUAAATT
SEQ ID No.14:AURKB siRNA B序列A/S:UUUAGGUCCACCUUGACGATG
SEQ ID No.15:AURKB siRNA C序列S:GCAAGUUUGGAAACGUGUATT
SEQ ID No.16:AURKB siRNA C序列A/S:UACACGUUUCCAAACUUGCCT
SEQ ID No.17:HDAC6 siRNA A序列S:CCGUGAGAGUUCCAACUUUTT
SEQ ID No.18:HDAC6 siRNA A序列A/S:AAAGUUGGAACUCUCACGGTG
SEQ ID No.19:HDAC6 siRNA B序列S:CAGUUUAUCUGCAUCCGAATT
SEQ ID No.20:HDAC6 siRNA B序列A/S:UUCGGAUGCAGAUAAACUGAG
SEQ ID No.21:HDAC6 siRNA C序列S:GGAGGGUCCUUAUCGUAGATT
SEQ ID No.22:HDAC6 siRNA C序列A/S:UCUACGAUAAGGACCCUCCGG
SEQ ID No.23:MEN1 siRNA A序列S:GAAGGUCUCCGAUGUCAUATT
SEQ ID No.24:MEN1 siRNA A序列A/S:UAUGACAUCGGAGACCUUCTT
SEQ ID No.25:MEN1 siRNA B序列S:GACCUACUAUCGGGAUGAATT
SEQ ID No.26:MEN1 siRNA B序列A/S:UUCAUCCCGAUAGUAGGUCTT
SEQ ID No.27:MEN1 siRNA C序列S:CCAUUGACCUGCACACCGATT
SEQ ID No.28:MEN1 siRNA C序列A/S:UCGGUGUGCAGGUCAAUGGAA
图7示出了siRNA对HepAD38.7细胞中AURKA、AURKB、Menin1、HDAC6和JAK2中的每一个的功能性敲低的结果。siRNA导致HBsAg水平和eHBV DNA水平低于阴性对照和对照样品。特别地,如图7中的左图所示,在HepAD38.7细胞中靶基因的基因敲低后通过ELISA测量的HBsAg水平显示出AURKB和HDAC6基因的良好降低。具有上清液中细胞外HBV DNA水平的右图示出了AURKB敲低中的最大降低。从这些数据可以看出,AURKB的敲低导致HBsAg和eHBV DNA水平的最大降低。JAK2的敲低也会导致两种测量的HBV水平降低。然而,其他三种靶标的敲低提供了不同的结果。这表明AURKA、AURKB、Menin1、HDAC6和JAK2的敲低导致HBV活性降低,并证明这些基因的敲低可导致有效的抗病毒作用。AURK抑制剂(TAK-901和CYC-116)和HDAC6抑制剂(Nexturastat A和Tubastatin A HCl)显示出显著更高的抗病毒活性并被进一步研究。
图8简要描述了用HBV感染细胞,用药物治疗,并且随后进行分析的方法的实验模型。将原代人肝细胞接种在胶原蛋白I包被的96孔板中(室温下30分钟)并且DMSO(1%)诱导。次日,在含有4%聚乙二醇8000(PEG-8000)和1%DMSO的培养基中用纯化的HBV以500的感染复数(MOI)(即感染因子(HBV)与感染目标(细胞)的比率)感染细胞(第0天)。次日,在不完全除去用过的培养基的情况下,通过洗涤3次来用力洗涤受感染的细胞以除去过量病毒,并用3μM浓度的测试化合物处理(第1天)。此外,在第3天收集上清液,用3μM浓度的测试化合物再次对细胞进行脉冲。第5天,收集上清液以用HBsAg ELISA进行分析,并且最后在第8天裂解细胞以用于DNA分离、eHBV分析和cccDNA分析。这允许比较化合物在第3天和第5天的效果。将一些细胞固定、透化并用抗HBcAg抗体染色,以通过IFA确定HBcAg水平。
图9示出了在受感染的原代人肝细胞(PHH)中HIT化合物与恩替卡韦(临床上用于治疗乙型肝炎的批准药物)相比的治疗结果。在第3天和第5天,结果显示在相同剂量下TAK-901、CYC-116、Nexturastat A和Tubastatin A HCl比恩替卡韦更多地降低HBsAg水平。特别地,CYC-116和Tubastatin A HCl显示出最低的HBsAg水平。原代人肝细胞中第3天和第5天的HBsAg水平数据显示,从第3天开始,在所有4种药物处理中均显示了显著降低,并持续到第5天。
图10表明Nexturastat A和Tubastatin A HCl具有与恩替卡韦相似的低毒性水平,而TAK-901和CYC-116具有更高的细胞毒性水平(使用细胞计数试剂盒8(CCK-8)确定)。特别地,AURKB抑制剂的细胞毒性在20-30%之间,而HDAC6抑制剂在这些PHH中的细胞毒性非常低。
图11示出了药物处理后第8天HBcAg的免疫荧光成像。可以看出,与恩替卡韦(ENTE)相当,六种hit化合物均降低了受感染的原代人肝细胞中的HBcAg水平。图11a示出了背景中具有E-钙粘蛋白的感染对照中的HBcAg水平。图11b示出了第8天药物处理细胞中的HBcAg水平。图11c示出了中间小图中HBcAg强度的量化数据。
图12示出了原代人肝细胞中的HIT对细胞培养上清液中的细胞外HBV DNA水平和HBVcc感染的原代人肝细胞的细胞裂解物中的cccDNA水平(通过qPCR测定)的影响。可以看出,TAK-901、CYC-116和AZ960比恩替卡韦更多地降低细胞外HBV DNA水平。TAK-901和CYC-116也提供了最低测量的cccDNA水平。可以看出,基于这两种测量,AURK和HDAC6抑制剂似乎具有最大的效果。
图13示出了使用Silencer Select siRNA和Lipofectamine 3000对候选基因进行RNAi功能敲低的结果。可以看出,对白蛋白产生几乎没有影响或没有影响,这意味着其不会对宿主细胞肝细胞功能产生不利影响,但会导致HBV前基因组RNA(pgRNA)水平降低,如通过qPCR测量的。特别地,在AURKB和HDAC6基因敲除中,pgRNA水平显著降低。pgRNA对照样品意味着模拟感染,即不存在HBV,因此pgRNA测量结果如预期的那样为零。
图14示出了AURKA、AURKB的敲低。HDAC6和MEN1降低细胞外HBV DNA水平和cccDNA水平(由qPCR测定),并且因此抑制受感染的原代人肝细胞中的HBV。特别地,当AURK和HDAC6下调时,细胞外HBV DNA和cccDNA水平显著下降。
将理解,不同基因和蛋白质的敲低对各种HBV生物标志物具有不同的影响,因此所有这些靶标都是可以是单独或组合的靶标,以开发用于乙型肝炎的有效治疗。
基于获得的结果,认为极光激酶A和B(AURKA和AURKB)以及HDAC6的敲低或抑制为治疗乙型肝炎提供了最可能(和/或最有效)的靶标。还有可能JAK2以及Menin-MLL相互作用的敲低或抑制可能是替代靶标。需要进一步研究AURK和HDAC6在病毒生命周期中的作用。不受理论束缚,已知HDAC6诱导Ac-微管蛋白的去脱酰化并使微管不稳定。认为AURK和HDAC6诱导其他病毒的核运输,并且在衣壳组装和病毒复制中存在微管的功能关联。AURK和HDAC6可能参与微管动力学,尤其是微管蛋白,并影响进入细胞的HBV向细胞核的转运。因此,可能的是AURK和HDAC的抑制或敲低可能会通过这些作用模式中的一种或两种导致HBV活性降低。
HIT化合物还可以与其他当前的乙型肝炎治疗方法组合,包括与目前使用的核苷类似物(NUC)组合以治疗乙型肝炎。可以使用的核苷类似物的例子包括恩替卡韦、替诺福韦、拉米夫定、阿德福韦和替比夫定或也与聚乙二醇化干扰素(PEG-IFN)组合治疗。这包括核苷类似物的任何前药形式或药学上可接受的盐。例如,替诺福韦在商业上以两种前药形式替诺福韦酯和替诺福韦艾拉酚胺存在。PEG-IFN疗法可以是聚乙二醇化干扰素α-2a或与聚乙二醇化干扰素-α-2b和聚乙二醇化干扰素-β-1a组合。
本文所述的结果表明,AURKA、AURKB、HDAC6、MEN1(以及因此的Menin-MLL相互作用)和JAK2是治疗乙型肝炎的可能生物学靶标,特别是AURKA、AURKB和HDAC6。通过使用RNAi方法抑制这些生物靶点或功能性敲低这些生物靶点的化合物可能是乙型肝炎的可能的治疗方法。
序列表
<110> 新加坡科技研究局 (Agency for Science, Technology and Research)
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<130> PPI22170205SG
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Claims (14)
1.一种选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物,用于治疗乙型肝炎。
2.根据权利要求1所述的化合物,其中,所述化合物选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
3.选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物在制造用于治疗乙型肝炎的药物中的用途。
4.根据权利要求3所述的用途,其中,所述化合物选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
5.一种治疗受试者中的乙型肝炎感染的方法,所述方法包括向所述受试者施用治疗有效剂量的选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物。
6.根据权利要求5所述的方法,其中,所述化合物选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
7.根据权利要求5至6中任一项所述的方法,还包括施用具有抗乙型肝炎病毒活性的核苷类似物或聚乙二醇化干扰素。
8.根据权利要求7所述的方法,其中,所述核苷类似物选自由恩替卡韦、替诺福韦、拉米夫定、阿德福韦、替比夫定以及所述化合物的任何前药和/或任何药学盐形式组成的组。
9.一种组合物,其包含选自由AZ960、CYC116、MI-3、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.28中任一个的小干扰RNA分子组成的组的化合物,以及具有抗乙型肝炎病毒活性的核苷类似物或聚乙二醇化干扰素。
10.根据权利要求9所述的组合物,其中,所述化合物选自由CYC116、Nexturastat A、TAK-901、Tubastatin A盐酸盐和包括SEQ ID No.5至SEQ ID No.22中任一个的小干扰RNA分子组成的组。
11.根据权利要求9至10中任一项所述的组合物,其中,所述核苷类似物选自由恩替卡韦、替诺福韦、拉米夫定、阿德福韦和替比夫定组成的组。
12.根据权利要求9至11中任一项所述的组合物,其用作药物。
13.根据权利要求12所述的组合物,其用于治疗乙型肝炎。
14.根据权利要求9至11中任一项所述的组合物在制造用于治疗乙型肝炎的药物中的用途。
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