CN117835984A - 使用胞苷脱氨酶抑制剂治疗rna病毒感染 - Google Patents
使用胞苷脱氨酶抑制剂治疗rna病毒感染 Download PDFInfo
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- CN117835984A CN117835984A CN202280022411.3A CN202280022411A CN117835984A CN 117835984 A CN117835984 A CN 117835984A CN 202280022411 A CN202280022411 A CN 202280022411A CN 117835984 A CN117835984 A CN 117835984A
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Abstract
本发明提供了用于通过施用或提供包含胞苷脱氨酶抑制剂(例如,四氢尿苷或西达尿苷)的组合物来治疗具有RNA病毒感染(例如,SARS‑CoV‑2)的受试者的组合物、系统、试剂盒和方法。
Description
本申请要求于2021年3月26日提交的美国临时申请序列号63/166,567的优先权,该美国临时申请通过引用整体并入本文。
技术领域
本发明提供了用于通过施用或提供包含胞苷脱氨酶抑制剂(例如,四氢尿苷或西达尿苷(cedazuridine))的组合物来治疗具有RNA病毒感染(例如,SARS-CoV-2)的受试者的组合物、系统、试剂盒和方法。
背景技术
冠状病毒疾病2019(COVID-19)是一种由严重急性呼吸综合征冠状病毒2(SARS-CoV-2或SARS2)引起的传染病。常见的症状包括发烧、咳嗽、疲劳、呼吸急促以及嗅觉和味觉丧失。尽管大多数病例导致轻度症状,但一些进展为异常形式的急性呼吸窘迫综合征(ARDS),其可能由细胞因子风暴、多器官衰竭、脓毒性休克和血凝块诱发。从暴露至症状发作的时间通常为约五天,但可在两天至十四天的范围内。病毒主要在密切接触期间在人之间传播,最常见的是通过咳嗽、打喷嚏和说话时产生的小飞沫传播。不太常见的是,人们可能通过接触被污染的表面然后再接触他们的面部而被感染。
发明内容
本发明提供了用于通过施用或提供包含胞苷脱氨酶抑制剂(例如,四氢尿苷或西达尿苷)的组合物来治疗具有RNA病毒感染(例如,SARS-CoV-2)的受试者的组合物、系统、试剂盒和方法。
在一些实施方案中,本文提供了治疗感染RNA病毒的受试者的方法,所述方法包括:向所述受试者施用组合物,或向所述受试者提供组合物使得所述受试者向其自身施用组合物;其中所述受试者感染RNA病毒;其中所述组合物包含胞苷脱氨酶抑制剂。
在其他实施方案中,本文提供了系统、试剂盒和制品,其包括:a)包含胞苷脱氨酶抑制剂的组合物;以及b)选自由以下各项组成的组的容器:i)气道施用设备,和ii)口服可摄取的剂型。在一些实施方案中,气道施用设备是喷雾器。在另外的实施方案中,口服可摄取的剂型是包含肠溶包衣的胶囊剂或丸剂。
在另外的实施方案中,本文提供了组合物,其包含:a)胞苷脱氨酶抑制剂;和b)嘧啶合成的抑制剂。
在另外的实施方案中,本文提供了体外组合物,其包含:a)胞苷脱氨酶抑制剂药物;和b)嘧啶合成的抑制剂。
在一些实施方案中,本文提供了系统或试剂盒,其包括:a)包含胞苷脱氨酶抑制剂药物的组合物;和b)用所述组合物治疗受试者的说明书,其中所述受试者感染RNA病毒。
在其他实施方案中,本文提供了包含口服可摄取的丸剂或胶囊剂的制品,其中所述口服可摄取的丸剂或胶囊剂包含:a)包含胞苷脱氨酶抑制剂的组合物;和b)包围所述组合物的肠溶包衣。在一些实施方案中,丸剂或胶囊剂包含胶囊剂,其中所述胶囊剂包含软凝胶。在另外的实施方案中,软凝胶包含明胶。
在某些实施方案中,胞苷脱氨酶抑制剂包含四氢尿苷、西达尿苷和/或二氮杂酮(diazepinone)核苷。在其他实施方案中,胞苷脱氨酶抑制剂包含式I化合物,其中式I如下:
或所述化合物的药学上可接受的盐,其中:
R1和R2独立地选自由以下各项组成的组:氢、卤基、氰基、硝基、巯基、羟基、甲酰基、羧基、COO(C1至C6直链或支链烷基)、COO(C1至C6直链或支链烯基)、COO(C1至C6直链或支链炔基)、CO(C1至C6直链或支链烷基)、CO(C1至C6直链或支链烯基)、CO(C1至C6直链或支链炔基)、C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基和C1至C6直链或支链烯氧基;其中C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基或C1至C6直链或支链烯氧基的每次出现能够独立地是未取代的或被一个至四个独立地选自由以下各项组成的组的取代基取代:卤基、羟基、氰基、硝基、甲酰基、羧基和巯基;
并且条件是:当R1和R2中的一个是—H时,则另一个不是—H、—OH或—CH2OH。
在某些实施方案中,RNA病毒是SAR2-COV-2。在其他实施方案中,进一步向受试者施用嘧啶合成抑制剂。在另外的实施方案中,嘧啶合成抑制剂包括特立氟胺。在一些实施方案中,嘧啶合成抑制剂包括来氟洛米。在另外的实施方案中,受试者是人。在其他实施方案中,受试者是动物(例如,狗、猫、马、牛、猪或其他家畜)。
在其他实施方案中,进一步向受试者施用病毒RNA聚合酶抑制剂。在另外的实施方案中,病毒RNA聚合酶抑制剂包括瑞德西韦。在另外的实施方案中,受试者是人。在其他实施方案中,受试者是动物(例如,狗、猫、马、牛、猪或其他家畜)。在另外的实施方案中,施用使得受试者接受每天每千克受试者约5-100mg胞苷脱氨酶抑制剂(例如,连续5-7天)。在其他实施方案中,施用是静脉内施用或经由受试者的气道施用。在另外的实施方案中,受试者向其自身施用组合物(例如,口服)。在另外的实施方案中,将组合物以口服剂型提供给受试者(例如,受试者通过口服向其自身施用组合物),并且其中所述组合物包含丸剂或胶囊剂。在特定的实施方案中,受试者接受每天每千克受试者约5-100mg胞苷脱氨酶抑制剂。
在另外的实施方案中,所述方法还包括:向受试者施用或提供抗凝血剂。在其他实施方案中,所述方法还包括:向受试者施用或提供不同的抗病毒剂。在另外的实施方案中,受试者使用呼吸机。在特定的实施方案中,组合物还包含生理上可耐受的缓冲剂。
附图说明
图1示出了SAR2的示意图,其显示SARS2基因组有1/3的尿苷碱基。
图2示出了冠状病毒可视化的尿苷(U)需求(U掺入核周冠状病毒RNA中)2。将感染MHV冠状病毒(95%类似于SARS2)的LR7细胞用标记的尿苷(乙炔基-尿苷)喂养1小时(数据来自Hagemeijerdr等人,Visualizing coronavirus RNA synthesis in time by usingclick chemist ry.J Virol.2012;86(10):5808-5816)。
图3显示,具有COVID19的患者的血清基本上耗竭了尿苷,即使胞苷同时增加。
图4示出了CDA使胞苷脱氨基以维持尿苷水平–显示的是细胞内CDA蛋白与胞苷之间的负相关,其稳定细胞尿苷量(对370个癌细胞系的分析–癌细胞系百科全书);p值:斯皮尔曼相关系数,双侧。
图5示出了A)CDA在感染SARS2的正常人支气管上皮细胞(NHBE)中相对于模拟感染的细胞上调。通过RNA-seq确定的基因表达TPM=每百万转录本-GSE147507。B)CDA是来自Covid19与非Covid19对照的人支气管上皮组织活检中单个最上调的嘧啶代谢酶-RNA seqGSE147507。所有已知的嘧啶挽救酶和从头酶。
图6示出了15名健康男性受试者中作为含有250mg THU/胶囊剂的三粒速释胶囊剂摄入的THU 750mg(约10mg/kg)的药代动力学(PK)–然后我们将这些结果扩展至另外22名女性和24名男性(NCT04086238)。A)浓度-时间曲线。THU对CDA的IC50为约0.3uM,对应于约74ng/mL的THU浓度。B)THU PK汇总统计。C)THU AUCinf与体重负相关。
图7示出了单次THU暴露使血清尿苷水平降低>50-80%。志愿者(3名男性;3名女性)间隔7天接受750mg的单次THU剂量,第1次剂量在空腹状态下,第2次在标准FDA餐食后。
图8示出了THU在体外抑制冠状病毒复制。将60%汇合度的正常肺上皮细胞用5pfu/ml VSV(Amiya Banerjee赠送)在37 0C下感染1小时。THU治疗24小时。对于噬菌斑测定,将上清液用于指示细胞系BHK21。通过QRT-PCR测量mRNA。平均值±SD。p值:双侧t检验。
图9示出了THU介导的C:U和CTP:UTP比率的增加预计会增加病毒基因组中的U→C错误。A)2小时THU对A549肺癌细胞中UTP和CTP水平的影响。通过LCMS/MS测定核苷酸水平。B)不同C:U比率下无效病毒复制的概率。图9计算:如果0<s<1,则P(s)=(1-P(L))[(λexp-λs)/1-e-λ);如果s=1,则P(s)=P(L);否则P(s)=0,si=1-ai/a0),ai和a0分别是突变病毒和参考病毒的生长速率。对随机单核苷酸(U→C)取代的适应度效应的分布的估计基于实验数据(定点诱变-Sanjua′n R等人,J.Virol,2010:9733–9748)。R-studio中的计算。
图10示出了临床相关浓度(常规Cmax为10-100uM)的特立氟胺有效抑制SARS2复制(红色),宿主细胞细胞毒性最小(绿色)。Xiong R等人,BioRXiv 2020(数据来自Xiong等人(2020)。靶向DHODH(一种从头嘧啶生物合成中的限速酶)的新型且有效的抑制剂是针对RNA病毒(包括新出现的冠状病毒SARS-CoV-2)的广谱抗病毒剂(bioRxiv11,983056)。
图11示出了分裂细胞大量利用从头嘧啶合成(CAD、DHODH、UMPS、CTPS2),其在向非分裂终末分化状态转变的过程中与CDA上调同时下调。示出了在从干细胞到终末分化的粒细胞的正常造血过程中的基因表达(微阵列基因表达,BloodSpot)。
图12示出了宿主细胞尿苷通过4种途径供应。分裂细胞中最重要的途径是从头嘧啶合成,其通过细胞分裂(通过MYC)活化。但是,SARS-CoV-2靶细胞是非分裂上皮细胞:CDA介导非分裂细胞中3个尿苷供应途径中的2个。通过抑制这两种尿苷供应途径,THU使非分裂细胞的尿苷供应量减少约90%,而没有已知的免疫抑制或其他副作用。
具体实施方式
本发明提供了用于通过施用或提供包含胞苷脱氨酶抑制剂(例如,四氢尿苷或西达尿苷)的组合物来治疗具有RNA病毒感染(例如,SARS-CoV-2)的受试者的组合物、系统、试剂盒和方法。
病毒绝对依赖于宿主细胞提供的核苷酸进行复制。例如,引起冠状病毒疾病2019(COVID-19)的SARS-CoV-2(SARS2)需要大量的宿主细胞尿苷-其基因组的1/3是尿苷(9597/29882bp),而1/6是胞苷(5492/29882)。此外,亚基因组正链RNA合成/病毒功能也需要尿苷。人嘧啶代谢挽救酶胞苷脱氨酶(CDA)通过全身性地和快速地将胞苷脱氨基成尿苷来促进这些SARS2尿苷需求。因此,在标准无毒剂量下,CDA抑制剂四氢尿苷(THU)将可用于全身挽救的尿苷减少多达90%。除了使SARS2缺乏复制所需的尿苷之外,较低的尿苷:胞苷比例可能增加低保真度SARS2 RNA聚合酶的错误。重要的是,THU在临床试验中被证明是安全的,这大概是由于人RNA聚合酶的高保真度,并且因为THU不会使脱氧核苷酸失衡。
THU对于治疗RNA病毒感染具有许多优点。例如,(i)THU减少非分裂宿主细胞、SARS2的靶细胞和许多其他病毒中的尿苷;(ii)THU具有公认的临床安全性,是非细胞毒性的,并保留长期病毒抑制和群体免疫所需的宿主免疫力;(iii)所提出的非限制性机制表明其具有泛冠状病毒抗病毒活性;(iv)THU可以口服递送,并且对于门诊病人、暴露后和世界范围的使用是切实可行和具有成本效益的,并且(v)增强病毒聚合酶抑制剂,而不增加毒性。总之,抑制CDA的THU可以用于有意义地治疗COVID-19、未来的大流行病(例如,尚未发现的RNA病毒),以及甚至非大流行的病毒疾病。
尽管理解该机制对于实践本发明不是必需的,并且本发明不限于任何特定的机制,但是提出施用THU(或其他胞苷脱氨酶抑制剂)可用于阻止/增加病毒复制中的错误,而不抑制宿主免疫,并因此使疾病减弱足够长的时间以产生有效的宿主免疫响应。此外,在某些实施方案中,THU(或其他胞苷脱氨酶抑制剂)有利地与从头嘧啶合成的抑制剂组合提供,因为THU能够降低它们的剂量和/或持续时间以缓和免疫抑制副作用,但可能会更深层次地使病毒缺乏尿苷。在某些实施方案中,使用THU或其他胞苷脱氨酶抑制剂(例如,通过口服施用)来治疗RNA病毒(诸如SARS2)、未来的大流行病(尚未发现的RNA病毒),以及甚至非大流行的病毒疾病。THU是非细胞毒性的,并且关键是能保留长期病毒抑制和群体免疫所需的免疫力。
用本文提供的方法治疗的RNA病毒的实例包括但不限于正粘病毒、丙型肝炎病毒(HCV)、埃博拉病、SARS、SARS2、流感、脊髓灰质炎、麻疹和逆转录病毒,包括成人型人T细胞亲淋巴病毒1型(HTLV-1)、人免疫缺陷病毒(HIV)、普通感冒、流感、MERS、COVID-19、登革热病毒、丙型肝炎、戊型肝炎、西尼罗热病毒、狂犬病病毒、脊髓灰质炎病毒、腮腺炎病毒和麻疹病毒。在特定的实施方案中,包膜病毒是选自B.1.351(“南非变异株”)或B.1.1.7(“英国变异株”)或“德尔塔(delta)”或“奥密克戎(omicron)”的SARS-CoV-2变异株。
在某些实施方案中,含有胞苷脱氨酶抑制剂的药物配制品以丸剂胶囊剂、凝胶帽等形式口服施用。在一些实施方案中,口服施用为5-100mg胞苷脱氨酶抑制剂(例如,THU)/千克受试者(例如,5...10...20...30...40...50...75...100mg/kg)。在某些实施方案中,本文提供了含有胞苷脱氨酶抑制剂(例如,四氢尿苷)的丸剂或胶囊剂。
胞苷脱氨酶抑制剂可以配制成药物配制品和/或药物。这些的实例包括但不限于冷冻干燥的粉末、旋转干燥的粉末或喷雾干燥的粉末、非晶形粉末、颗粒、沉淀物或微粒。对于注射,配制品可以任选地含有稳定剂、pH调节剂、表面活性剂、生物可用性调节剂和这些的组合。在某些实施方案中,将胞苷脱氨酶抑制剂与缓冲液(例如,磷酸盐缓冲盐水)混合。
胞苷脱氨酶抑制剂可以通过经鼻或口吸入而施用于肺部。合适的用于吸入的药物配制品包括溶液、喷雾剂、干燥粉末或气雾剂,其含有任何适合的溶剂和任选的其他化合物,诸如但不限于稳定剂、抗菌剂、抗氧化剂、pH调节剂、表面活性剂、生物可用性调节剂和这些的组合。用于吸入施用的配制品含有赋形剂,例如,乳糖、聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐。水性和非水性气雾剂通常用于通过吸入递送THU。
通常,水性气雾剂通过将胞苷脱氨酶抑制剂(例如,四氢尿苷)的水溶液或悬浮液与常规药学上可接受的载体和稳定剂一起配制来制备。载体和稳定剂随特定化合物的要求而变化,但通常包括非离子型表面活性剂(例如,吐温(TWEEN)、普朗尼克(Pluronic)或聚乙二醇)、无害蛋白质类血清白蛋白、脱水山梨醇酯、油酸、卵磷脂、甘氨酸等氨基酸、缓冲剂、盐、糖或糖醇。气雾剂通常由等渗溶液制备。非水悬浮液(例如,在碳氟化合物推进剂中)也可用于递送胞苷脱氨酶抑制剂(例如,四氢尿苷)。
使用吸入器、雾化器、加压包装或喷雾器和合适的推进剂,例如但不限于加压的二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氮气、空气或二氧化碳,方便地递送含有根据本发明使用的胞苷脱氨酶抑制剂的气雾剂。在加压气雾剂的情况下,剂量单位可以通过提供阀门以递送计量的量来控制。可以配制用于吸入器或吹入器的例如明胶的胶囊剂和药筒,其含有胞苷脱氨酶抑制剂与合适的粉末基质(诸如乳糖或淀粉)的粉末混合物。使用声波喷雾器递送本发明的气雾剂是有利的,因为喷雾器将药剂暴露于剪切力的程度降至最低,所述剪切力可能会导致化合物降解。
对于经鼻给药,具有胞苷脱氨酶抑制剂的药物配制品和药物可以是喷雾剂、滴鼻剂或气雾剂,其含有适当的溶剂和任选的其他化合物,诸如但不限于稳定剂、抗菌剂、抗氧化剂、pH调节剂、表面活性剂、生物可用性调节剂和这些的组合。对于以滴鼻剂形式施用,胞苷脱氨酶抑制剂可以配制成油性溶液或凝胶。对于鼻气雾剂的施用,可以使用任何合适的推进剂,包括压缩空气、氮气、二氧化碳或烃基低沸点溶剂。
用于本发明的胞苷脱氨酶抑制剂的局部(包括口腔和舌下)或经皮或口服施用的剂型包括粉末、喷雾剂、丸剂、凝胶帽、软膏、糊剂、霜剂、洗剂、凝胶、溶液和贴片。可以在无菌条件下混合胞苷脱氨酶抑制剂与药学上可接受的载体或赋形剂以及与可能需要的任何防腐剂或缓冲剂。可以例如用赋形剂诸如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物制备粉末和喷雾剂。软膏、糊剂、乳膏剂和凝胶也可以含有赋形剂,诸如动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌,或其混合物。
在某些实施方案中,本文的丸剂或胶囊剂包含明胶包封的剂型(例如,软凝胶)。在某些实施方案中,脱氨酶抑制剂的明胶包囊由明胶、甘油、水和任选的焦糖构成。在特定的实施方案中,本文的丸剂和胶囊剂用肠溶包衣包被(例如,以避免胃的酸性环境,并在受试者的小肠中释放大部分胞苷脱氨酶抑制剂)。在一些实施方案中,肠溶包衣包含聚合物屏障,所述聚合物屏障防止肠溶包衣在胃环境中溶解或崩解,从而允许本文的胞苷脱氨酶抑制剂到达小肠。肠溶包衣的实例包括但不限于丙烯酸甲酯-甲基丙烯酸共聚物;邻苯二甲酸醋酸纤维素(CAP);醋酸琥珀酸纤维素;羟丙基甲基纤维素邻苯二甲酸酯;羟丙基甲基纤维素醋酸酯琥珀酸酯(醋酸琥珀羟丙甲纤维素);聚醋酸乙烯邻苯二甲酸酯(PVAP);甲基丙烯酸甲酯-甲基丙烯酸共聚物;虫胶;醋酸纤维素偏苯三酸酯;海藻酸钠;玉米蛋白;COLORCON和肠溶包衣水溶液(乙基纤维素、中链甘油三酯[椰子]、油酸、海藻酸钠、硬脂酸)(例如,包衣软凝胶)。另外的肠溶包衣描述于Hussan等人,IOSR Journal of Pharmacy,e-ISSN:2250-3013,p-ISSN:2319-4219,第2卷第6期,2012年11月-12月,第05-11页中,所述文献通过引用整体并入本文中,并且特别是其对肠溶包衣的描述。
透皮贴剂具有额外的优点,即提供胞苷脱氨酶抑制剂到身体的受控递送。此类剂型可以通过将胞苷脱氨酶抑制剂溶解或分散于适当介质中来制备。也可以使用吸收增强剂以增加胞苷脱氨酶抑制剂(例如,THU)穿过皮肤的通量。此类通量的速率可以通过提供速率控制膜或将所述化合物分散于聚合物基质或凝胶中来控制。
除上文所描述的那些代表性剂型以外,药学上可接受的赋形剂和载体对于本领域技术人员而言通常是已知的并且因此包括在本发明中。此类赋形剂和载体描述于例如"Remingtons Pharmaceutical Sciences"Mack Pub.Co.,New Jersey(1991),所述文献通过引用并入本文。
可以根据受试者的疾病病状、年龄、体重、一般健康状况、性别和饮食、给药间隔、施用途径、分泌速率和药物组合来调节胞苷脱氨酶抑制剂的特定剂量。含有有效量的任何上述剂型都恰好在常规实验的界限之内,并且因此也恰好在本发明的范围内。
在特定的实施方案中,可以将治疗过程同时施用于受试者,即,将单独剂量的本文的胞苷脱氨酶抑制剂和辅助治疗剂(例如,嘧啶合成抑制剂)在一定时间间隔内分开施用,使得胞苷脱氨酶抑制剂可以与附加治疗剂一起发挥作用。例如,一种组分可每天施用一次、每天施用两次或每天施用三次,而其他组分可每周施用一次或两次或三次。换句话说,即使不同时或在同一天内施用治疗剂,给药方案也是同时进行的。
实施例
实施例1
用于COVID-19治疗的四氢尿苷
迫切需要一种口服施用并且对于广泛使用足够安全的确切COVID-19治疗剂。COVID-19是世界紧急事件。目前还没有批准的治疗COVID-19的确切口服抗病毒剂(例如,将腺苷类似物瑞德西韦静脉内施用给住院患者)。该实施例表明,THU是满足这个需要的候选者。
SARS2需要大量的宿主细胞尿苷才能进行复制,并且酶CDA供应了这些需要。病毒复制绝对依赖于从宿主细胞中劫持的核苷酸:特别地,SARS2需要大量的宿主细胞尿苷才能进行复制和引起疾病-其基因组的1/3(9597/29882bp)是尿苷,而1/6(5492/29882)是胞苷(图1、2)(图2数据来自Hagemeijer等人,Visualizing coronavirus RNA synthesis intime by using click chemistry.J Virol.2012;86(10):5808-5816)。此外,亚基因组正链RNA合成和病毒功能也需要尿苷(2)。因此,COVID-19患者的血清耗竭了尿苷(图3)。人胞苷脱氨酶(CDA)是嘧啶代谢酶,其通过快速地和全身性地将胞苷脱氨基成尿苷来促进这些高尿苷需求–CDA以胞苷水平为代价维持尿苷水平作为生理优先级(图4)。因此,与由SARS2感染引起的尿苷的全身性耗竭一致,并根据由SARS2感染引起的尿苷的全身性耗竭预期(图3),CDA是在COVID-19患者的支气管活检中异常上调的嘧啶代谢酶,并且在体外被SARS2感染的支气管上皮细胞中也上调(图5)。
THU是一种安全且有效的CDA抑制剂。THU是一种通过与CDA同源四聚体的每个亚基可逆地结合进行的强效的、可逆的CDA抑制剂,其中Ki为约10-7M并且IC50为约0.34μM(7)。
THU临床药代动力学。在体重介于60-100kg之间的15名健康男性志愿者中,作为含有THU 250mg/胶囊剂的三粒速释胶囊剂摄入的固定剂量为750mg的单独THU产生的THUCmax为2–8uM(500–2000ng/mL)(图6A、B)。这些浓度明显高于用于抑制CDA的IC50(0.3uM)(35)。施用后约3小时达到Tmax(图6A、B)。本研究中观察到的THU Cmax和AUCinf的变化与体重相关(图6C)。我们继续评价了另外22名女性和24名男性在空腹以及进食状态下的THU药代动力学,结果与这些结果重复(NCT04086238)。排泄的主要途径是通过肾脏,约50%的施用药物在24小时内排泄,并且在48小时内100%消除(36)。
THU临床药效学。我们通过测量标准临床剂量(图7)对血清尿苷水平的影响评价了THU的临床药效学。750mg的单次THU剂量使男性和女性在空腹和进食状态下的血清尿苷水平降低50-90%,同时增加血清胞苷水平(即,逆转通常的全身尿苷:胞苷比率)(图7)。我们和其他人还通过THU对共同施用的胞苷类似物的脱氨基的影响测量了THU的临床药效学,并发现胞苷类似物的脱氨基减少约90%(4,5,37,38)。
THU临床安全性。尽管THU不是批准的药物,但我们的研究小组和美国国家癌症研究所(National Cancer Institute)已在多项1期和2期临床试验(血液学和肿瘤学临床试验)中对其进行了广泛评价。这几项临床评价和广泛的IND临床前动物研究已经证实了在抑制CDA方面药效学活性较高的剂量下(36-44)和超过1年的施用持续时间内的优异安全性(总结于表1中)。
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THU抑制冠状病毒体外复制。我们评价了THU作为单一剂对冠状病毒体外复制的作用。临床相关浓度的THU显著抑制人肺上皮细胞中的冠状病毒(VSV)复制,如通过噬菌斑测定和通过QRT-PCR所测量的(图8)。
还预计降低尿苷:胞苷比率会增加病毒复制中的错误,从而促进免疫识别。在大流行期间对SARS2的连续测序已经证明了渐进的C→U突变,这归因于选择逃避宿主APOBEC3抗病毒编辑(6,45)。THU改变尿苷:胞苷和UTP:CTP化学计量,使得易错病毒RNA聚合酶更有可能执行U→C突变,这将重新引入对APOBEC3抗病毒编辑和先天免疫响应的脆弱性(6,45)(图9A、B)。
降低宿主细胞尿苷的其他药物在科学和临床上被证实抑制SARS2和其他RNA病毒16-24的复制,但是THU具有优势。宿主细胞尿苷通过4种途径供应:在分裂细胞中,最重要的来源是从谷氨酰胺和天冬氨酸基本结构单元从头合成,其速率受DHODH酶的限制。通用药物特立氟胺及其前药来氟洛米(分别被批准用于治疗多发性硬化和类风湿性关节炎)是降低活跃增殖细胞中的尿苷量的DHODH抑制剂:DHODH抑制剂被可重复地证明在体外抑制包括SARS2在内的多种病毒的复制(在指数增殖细胞中进行的测定)(图10-来自Xiong等人(2020)的数据。靶向DHODH(一种从头嘧啶生物合成中的限速酶)的新型且有效的抑制剂是针对RNA病毒(包括新出现的冠状病毒SARS-CoV-2)的广谱抗病毒剂(bioRxiv 11,983056)。此外,在几个感染CMV的肾移植患者病例系列中,来氟洛米清除病毒和/或产生临床改善(n=4、2517、26和3127)(27-30)。然而,以此方式抑制从头合成的一个主要限制是对增殖宿主细胞(例如,免疫细胞)和恢复上皮组织的毒性。然而,存在先前未解决的另一关键限制:非分裂宿主细胞,例如被SARS2感染的呼吸道上皮细胞(34),不依赖于从基本结构单元诸如谷氨酰胺从头合成核碱基。相反,这些非分裂细胞从胞外空间回收核碱基(图11、12)。因此,宿主细胞核苷酸从头合成的抑制剂可抑制免疫/组织修复,但无法抑制SARS2复制。这种限制难以在临床前体外研究中识别,临床前体外研究出于实际技术原因使用指数增殖细胞(例如,A549肺癌细胞),但这种限制将可能破坏靶向非分裂上皮细胞的病毒(例如,SARS2)的体内治疗。因此,THU可能是一种更好的广谱抗病毒治疗。
THU可以合理地与其他抗病毒药物组合。尽管THU以前没有被评价为用于治疗病毒性(或其他)疾病的单独实体,但是它已经在若干临床前研究中用于阻断共同施用的抗病毒胞苷类似物(例如,嘧啶核苷类似物)的代谢,以抑制病毒聚合酶(9-13)。在某些实施方案中,THU与瑞德西韦组合用于治疗RNA病毒感染。在其他实施方案中,将THU与从头嘧啶合成抑制剂(例如,特立氟胺,其被批准用于治疗多发性硬化)组合,因为该组合更深层次地耗竭宿主细胞尿苷碱基(先前在指数增殖细胞中显示(46)),以潜在地更广泛地限制病毒复制,同时允许减少特立氟胺剂量和/或持续时间,以保留免疫力(表2)。
表2.THU单剂和与特立氟胺(或瑞德西韦,未在该表中示出,用于治疗SARS2或其他病毒)组合的概述的基本原理。
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本申请中提及的所有出版物和专利均通过引用并入本文。在不脱离本发明的范围和精神的情况下,本发明的所述方法和组合物的各种修改和变化对于本领域技术人员将是显而易见的。虽然已结合特定优选实施方案描述了本发明,但应理解,要求保护的本发明不应不适当地局限于此类特定实施方案。实际上,用于进行本发明的所述方式的各种修改对于相关领域技术人员而言是明显的,并且旨在包含在以下权利要求书的范围内。
Claims (33)
1.一种治疗感染RNA病毒的受试者的方法,其包括:
向受试者施用组合物,或向所述受试者提供所述组合物使得所述受试者向其自身施用所述组合物;
其中所述受试者感染RNA病毒;
其中所述组合物包含胞苷脱氨酶抑制剂。
2.如权利要求1所述的方法,其中所述胞苷脱氨酶抑制剂包括四氢尿苷、西达尿苷和/或二氮杂酮核苷。
3.如权利要求1所述的方法,其中所述胞苷脱氨酶抑制剂包含式I化合物,其中式I如下:
或所述化合物的药学上可接受的盐,其中:
R1和R2独立地选自由以下各项组成的组:氢、卤基、氰基、硝基、巯基、羟基、甲酰基、羧基、COO(C1至C6直链或支链烷基)、COO(C1至C6直链或支链烯基)、COO(C1至C6直链或支链炔基)、CO(C1至C6直链或支链烷基)、CO(C1至C6直链或支链烯基)、CO(C1至C6直链或支链炔基)、C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基和C1至C6直链或支链烯氧基;其中C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基或C1至C6直链或支链烯氧基的每次出现能够独立地是未取代的或被一个至四个独立地选自由以下各项组成的组的取代基取代:卤基、羟基、氰基、硝基、甲酰基、羧基和巯基;
并且条件是:当R1和R2中的一个是—H时,则另一个不是—H、—OH或—CH2OH。
4.如权利要求1所述的方法,其中所述RNA病毒是SAR2-COV-2或其他冠状病毒。
5.如权利要求1所述的方法,其中进一步向所述受试者施用嘧啶合成抑制剂。
6.如权利要求5所述的方法,其中所述嘧啶合成抑制剂包括特立氟胺。
7.如权利要求5所述的方法,其中所述嘧啶合成抑制剂包括来氟洛米。
8.如权利要求1所述的方法,其中进一步向所述受试者施用病毒RNA聚合酶的抑制剂。
9.如权利要求8所述的方法,其中所述病毒RNA聚合酶抑制剂是瑞德西韦。
10.如权利要求1所述的方法,其中所述受试者是人。
11.如权利要求1所述的方法,其中所述受试者是动物。
12.如权利要求1所述的方法,其中所述施用使得所述受试者接受每天每千克所述受试者约5-100mg所述胞苷脱氨酶抑制剂。
13.如权利要求1所述的方法,其中所述施用是静脉内施用或口服施用或经由所述受试者的气道进行。
14.如权利要求1所述的方法,其中所述受试者向其自身口服施用所述组合物,并且其中所述组合物包含丸剂或胶囊剂,并且其中所述受试者接受每天每千克所述受试者约5-100mg所述胞苷脱氨酶抑制剂。
15.如权利要求1所述的方法,其还包括:向所述受试者施用或提供抗凝血剂。
16.如权利要求1所述的方法,其还包括:向所述受试者施用或提供不同的抗病毒剂。
17.如权利要求1所述的方法,其中所述受试者使用呼吸机。
18.如权利要求1所述的方法,其中所述组合物还包含生理上可耐受的缓冲剂。
19.一种系统、试剂盒或制品,其包括:
a)包含胞苷脱氨酶抑制剂的组合物;以及
b)选自由以下各项组成的组的容器:
i)气道施用设备,和
ii)口服可摄取的剂型。
20.如权利要求19所述的系统、试剂盒或制品,其中所述气道施用设备是喷雾器。
21.如权利要求19所述的系统、试剂盒或制品,其中所述口服可摄取的剂型是包含肠溶包衣的胶囊剂或丸剂。
22.如权利要求19所述的系统、试剂盒或制品,其中所述胞苷脱氨酶抑制剂包括四氢尿苷、西达尿苷和/或二氮杂酮核苷。
23.如权利要求19所述的系统、试剂盒或制品,其中所述胞苷脱氨酶抑制剂包含式I化合物,其中式I如下:
或所述化合物的药学上可接受的盐,其中:
R1和R2独立地选自由以下各项组成的组:氢、卤基、氰基、硝基、巯基、羟基、甲酰基、羧基、COO(C1至C6直链或支链烷基)、COO(C1至C6直链或支链烯基)、COO(C1至C6直链或支链炔基)、CO(C1至C6直链或支链烷基)、CO(C1至C6直链或支链烯基)、CO(C1至C6直链或支链炔基)、C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基和C1至C6直链或支链烯氧基;其中C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基或C1至C6直链或支链烯氧基的每次出现能够独立地是未取代的或被一个至四个独立地选自由以下各项组成的组的取代基取代:卤基、羟基、氰基、硝基、甲酰基、羧基和巯基;
并且条件是:当R1和R2中的一个是—H时,则另一个不是—H、—OH或—CH2OH。
24.一种组合物,其包含:
a)胞苷脱氨酶抑制剂;以及
b)RNA病毒。
25.如权利要求24所述的组合物,其中所述胞苷脱氨酶抑制剂包括四氢尿苷、西达尿苷和/或二氮杂酮核苷。
26.如权利要求24所述的组合物,其中所述胞苷脱氨酶抑制剂包含式I化合物,其中式I如下:
或所述化合物的药学上可接受的盐,其中:
R1和R2独立地选自由以下各项组成的组:氢、卤基、氰基、硝基、巯基、羟基、甲酰基、羧基、COO(C1至C6直链或支链烷基)、COO(C1至C6直链或支链烯基)、COO(C1至C6直链或支链炔基)、CO(C1至C6直链或支链烷基)、CO(C1至C6直链或支链烯基)、CO(C1至C6直链或支链炔基)、C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基和C1至C6直链或支链烯氧基;其中C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基或C1至C6直链或支链烯氧基的每次出现能够独立地是未取代的或被一个至四个独立地选自由以下各项组成的组的取代基取代:卤基、羟基、氰基、硝基、甲酰基、羧基和巯基;
并且条件是:当R1和R2中的一个是—H时,则另一个不是—H、—OH或—CH2OH。
27.一种体外组合物,其包含:
a)胞苷脱氨酶抑制剂;以及
b)嘧啶合成的抑制剂。
28.一种系统或试剂盒,其包括:
a)包含胞苷脱氨酶抑制剂的组合物;和
b)用所述组合物治疗受试者的说明书,其中所述受试者感染了RNA病毒。
29.一种制品,其包含口服可摄取的丸剂或胶囊剂,其中所述口服可摄取的丸剂或胶囊剂包含:
a)包含胞苷脱氨酶抑制剂的组合物;以及
b)包围所述组合物的肠溶包衣。
30.如权利要求29所述的制品,其中所述丸剂或胶囊剂包含胶囊剂,其中所述胶囊剂包含软凝胶。
31.如权利要求30所述的制品,其中所述软凝胶包含明胶。
32.如权利要求29所述的制品,其中所述胞苷脱氨酶抑制剂包括四氢尿苷、西达尿苷和/或二氮杂酮核苷。
33.如权利要求29所述的制品,其中所述胞苷脱氨酶抑制剂包含式I化合物,其中式I如下:
或所述化合物的药学上可接受的盐,其中:
R1和R2独立地选自由以下各项组成的组:氢、卤基、氰基、硝基、巯基、羟基、甲酰基、羧基、COO(C1至C6直链或支链烷基)、COO(C1至C6直链或支链烯基)、COO(C1至C6直链或支链炔基)、CO(C1至C6直链或支链烷基)、CO(C1至C6直链或支链烯基)、CO(C1至C6直链或支链炔基)、C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基和C1至C6直链或支链烯氧基;其中C1至C6直链或支链烷基、C1至C6直链或支链烯基、C1至C6直链或支链炔基、C1至C6直链或支链烷氧基或C1至C6直链或支链烯氧基的每次出现能够独立地是未取代的或被一个至四个独立地选自由以下各项组成的组的取代基取代:卤基、羟基、氰基、硝基、甲酰基、羧基和巯基;
并且条件是:当R1和R2中的一个是—H时,则另一个不是—H、—OH或—CH2OH。
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