CN114786659A - 用于治疗汉坦病毒感染的mek抑制剂 - Google Patents
用于治疗汉坦病毒感染的mek抑制剂 Download PDFInfo
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- CN114786659A CN114786659A CN202080084724.2A CN202080084724A CN114786659A CN 114786659 A CN114786659 A CN 114786659A CN 202080084724 A CN202080084724 A CN 202080084724A CN 114786659 A CN114786659 A CN 114786659A
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Abstract
本发明涉及能够显示一种或多种有益治疗效果的MEK抑制剂。所述MEK抑制剂可用于预防和/或治疗汉坦病毒感染。
Description
背景技术
汉坦病毒(或正汉坦病毒)是布尼亚病毒(Bunyavirales)目汉坦病毒(Hantaviridae)科中的单链、包膜、负链RNA病毒。迄今为止,已知有28种致病性汉坦病毒。汉坦病毒的种类因它们的地理位置而不同。在欧洲,流行的汉坦病毒是普马拉病毒(Puumala virus),而在美国,流行的是安第斯病毒(Andes virus)和辛诺柏病毒(SinNombre virus)。在亚洲,发现的是汉坦病毒和汉城病毒(Seoul virus)。汉坦病毒的天然宿主是啮齿动物、地鼠和蝙蝠,然而,在天然宿主中没有发现临床症状。汉坦病毒的传播主要通过雾化的啮齿动物排泄物(尿、唾液、粪便)发生,然而,在2005和2019年,南美报道了安第斯病毒的人与人传播(Martinez VP,Bellomo C,San Juan J,Pinna D,Forlenza R,ElderM,Padula PJ(2005)."Person-to-person transmission of Andes virus".EmergingInfectious Diseases;11(12):1848–1853)。对于汉坦病毒,在人中的潜伏期持续长达数周。
汉坦病毒感染存在全球威胁,因为这些感染与高死亡率相关,并且可用的治疗非常有限。在人类中,汉坦病毒感染本身呈现两种临床表现。第一种是汉坦病毒肾综合征出血热(HFRS),其中死亡率是12%,第二种是汉坦病毒肺综合征(HPS),其中死亡率是40%。疾病的严重程度取决于致病的汉坦病毒种类和病毒载量。例如,已知严重病程由汉坦病毒(Hantaan virus)、多布拉瓦-贝尔格莱德病毒(Dobrava-Belgrad virus)、辛诺柏病毒和安第斯病毒引起,而中度病程更可能是由例如普马拉病毒或萨列马岛病毒(Saaremaa virus)引起的。每年至少记载有100,000个HFRS病例。2004年,仅在中国每年就有40,000-60,000例(Zhang等人2004,Lee等人1996,Lee等人1998),相比之下,欧洲有约9,000例(Vapalatti等人2003,Heyman等人2009,Heyman等人2011)。
目前还没有FDA或WHO批准的疫苗或抗病毒剂可用于治疗或预防汉坦病毒感染。自1990年以来,称为Hantavax的疫苗已经在研究中,并且在韩国使用,但是还没有被广泛批准,并且具有有限的效力。由于在高密封下大规模生产的危险以及未解决的疫苗功效问题,灭活病毒疫苗并未被推行。许多实验室已经致力于研制通过DNA载体或作为重组蛋白递送病毒抗原的疫苗,但是迄今为止这些疫苗都没有显示出有效性。
此外,除了缓解疾病症状外,目前还没有批准用于HPS或HFRS的治疗方法。可能使用的唯一药物是利巴韦林,但其有效性仍然未知。特别是控制RNA病毒(如汉坦病毒)的一个问题是由病毒聚合酶的高故障率导致的病毒适应性,这使得合适疫苗的生产以及抗病毒物质的开发非常困难。因此,已知大多数已知的抗病毒药物会导致单个RNA病毒产生耐药性。
由于非常小的基因组,因此复制所必需的功能编码能力有限,所有病毒高度依赖于它们宿主细胞的功能。通过对病毒复制所必需的此种细胞功能施加影响,可能会对感染细胞中的病毒复制产生负面影响。在这种情况下,病毒不可能通过适应,特别是通过突变来替代缺乏的细胞功能,以便因此逃避选择压力。这可能已经在对细胞激酶和甲基转移酶具有相对非特异性的抑制剂的甲型流感病毒中得到证实(Scholtissek and Müller,ArchVirol 119,111-118,1991)。
本领域已知细胞具有多个信号传输路径,通过这些路径作用于细胞的信号被传输到细胞核中。因此,细胞能够对外部刺激作出反应,并通过细胞增殖、细胞活化、分化或受控细胞死亡作出反应。这些信号传输路径的共同点是它们含有至少一种激酶,该激酶通过磷酸化激活至少一种蛋白质,随后传输信号。当观察病毒感染后诱导的细胞过程时,发现大量DNA和RNA病毒在感染的宿主细胞中优先激活确定的信号传输路径,即所谓的Raf/MEK/ERK激酶信号传输路径(Benn等人,J Virol 70,4978-4985,1996;Bruder and Kovesdi,JVirol 71,398-404,1997;Popik and Pitha,Virology 252,210-217,1998;Rodems andSpector,J Virol 72,9173-9180,1998)。该信号传输路径是细胞中最重要的信号传输路径之一,并且在增殖和分化过程中起重要作用。生长因子诱导的信号通过连续磷酸化从丝氨酸/苏氨酸激酶Raf传递至双特异性激酶MEK(MAP激酶/ERK激酶)并最终传递至激酶ERK(胞外信号调节激酶)。而作为Raf的激酶底物,只有MEK已知,并且ERK亚型被确定为MEK的唯一底物,ERK能够磷酸化全部底物。例如,这些属于转录因子,细胞基因表达由此会直接受到影响(Cohen,Trends in Cell Biol 7,353-361,1997;Robinson and Cobb,Curr.Opin.CellBiol 9,180-186,1997;Treisman,Curr.Opin.Cell Biol 8,205-215,1996)。
鉴于现有技术,显然需要进一步的化合物和组合物有效预防和治疗病毒性疾病,特别是由汉坦病毒引起的疾病。
在这方面,正在进行的关于MEK抑制剂在治疗其它病毒性疾病,特别是流感中有用性的研究已经揭示,这类化合物避免了标准抗病毒治疗的缺点,这是因为它针对的是宿主细胞的细胞成分而不是病毒本身。由于这个原因,尚未观察到对MEK抑制剂的耐药性。WO2001/076570提供通过MEK抑制剂治疗或预防由(-)RNA病毒,特别是流感病毒引起的感染的概念。WO2014/056894提供用于治疗或预防流感病毒感染的特异性MEK抑制剂,例如AZD-6244、AZD-8330、RDEA-119、GSK-1120212(曲美替尼)、GDC0973(钴美替尼)、CI-1040、PD-0325901、RO-5126766、MSC1936369(AS703026)。WO2015/173788A1公开了MEK抑制剂用在治疗流感病毒和细菌共感染的方法中。此外,WO 2019/076947公开了一种新的MEK抑制剂PD-0184264(也称为ATR-002)用于预防和/或治疗流感病毒感染的方法中。
然而,这些文献中没有一个显示MEK抑制剂可以用于汉坦病毒感染,并且仍然迫切需要提供用于治疗和预防汉坦病毒感染的组合物和化合物。
发明内容
在本发明中,发现MEK抑制剂用在汉坦病毒感染的治疗或预防中导致病毒感染得到有效治疗。具体而言,当向汉坦病毒感染的小鼠施用MEK抑制剂CI-1040或PD-0184264时,观察到病毒载量强烈降低。
因此,本发明涉及一种用于治疗或预防哺乳动物,优选人或啮齿动物中汉坦病毒感染的MEK抑制剂。
在本发明的上下文中,所述MEK抑制剂可以选自CI-1040、PD-0184264、GSK-1120212、GDC-0973、PLX-4032、AZD6244、AZD8330、AS-703026、RDEA-119、RO-5126766、RO-4987655、PD-0325901、TAK-733、AS703026、PD98059和PD184352或其药学上可接受的盐或代谢物。在一个优选的方面,所述MEK抑制剂是CI-1040或PD-0184264。
在人类患者中,当所述患者表现出汉坦病毒肾综合征出血热(HFRS)或汉坦病毒肺综合征(HPS)的症状时,能够施用MEK抑制剂来治疗汉坦病毒感染。在这些情况下,在观察到HFRS或HPS的第一症状后高达12小时、高达24小时、高达48小时、高达72小时或4至10天之间施用所述MEK抑制剂。
还可以向已经与啮齿动物或啮齿动物排泄物接触或处于汉坦病毒爆发普遍的区域中的人类受试者施用所述MEK抑制剂用于预防汉坦病毒感染。
当人类受试者在已知存在导致HFRS或HPS的汉坦病毒感染的区域中一直生活或旅行时,特别需要施用MEK抑制剂来治疗或预防汉坦病毒感染。
这种汉坦病毒感染可以是由美洲物种如黑克里克管病毒(BCCV)、纽约正汉坦病毒(NYV)、单门哈拉病毒(MGLV)、诺伯斯正汉坦病毒(SNV)或安德斯病毒引起的汉坦或东巴拉夫病毒感染,或者汉坦病毒感染。
优选地,本发明所述的供使用的MEK抑制剂可口服或经由吸入给药。
另一方面,考虑以MEK抑制剂治疗啮齿动物群体,以预防与啮齿动物接触的人感染。在此种用途中,所述MEK抑制剂可以通过吸入,例如通过环境喷雾来给药。
附图说明
图1示出在CI-1040的存在下与溶剂对照组相比较实现了>2log10-步的显著病毒滴度降低。这相当于病毒滴度降低>99%。
图2示出在ATR-002的存在下与溶剂对照组相比较实现了>1,5log10步的病毒滴度降低。这相当于病毒滴度降低>90%。
图3示出在用75mg/kg/天的ATR-002处理动物的肺时,在感染后第7天和第10天没有检测到病毒。
图4示出在用75mg/kg/天的ATR-002处理动物的肾时,在感染后第7天和第10天没有检测到病毒。
具体实施方式
以下描述包括在理解本发明时可能有用的信息。不承认本文提供的任何信息是现有技术或与目前要求保护的发明相关,也不承认任何具体或隐含引用的出版物是现有技术。
本文所用的“MEK抑制剂”通过抑制MEK(促分裂原活化蛋白激酶)来抑制细胞或受试者中的促有丝分裂信号级联Raf/MEK/ERK。这种信号级联被许多病毒(特别是流感病毒)劫持,以促进病毒复制。因此,在MEK瓶颈处特异性阻断Raf/MEK/ERK通路会损害病毒(尤其是流感病毒)的生长。另外,MEK抑制剂对人体毒性低,不良副作用小。也没有诱导病毒耐药性的趋势(Ludwig,2009)。一种特别优选的MEK抑制剂是PD-0184264,也称为ATR-002。
优选地,所述MEK抑制剂选自CI-1040、PD-0184264、GSK-1120212、GDC-0973、PLX-4032、AZD6244、AZD8330、AS-703026、RDEA-119、RO-5126766、RO-4987655、PD-0325901、TAK-733、AS703026、PD98059和PD184352或其药学上可接受的盐或代谢物。这些MEK抑制剂是本领域已知的,例如,如Fremin和Meloche(2010),J.Hematol.Oncol.11;3:8的表1所述。以下示出PD-0184264和CI-1040的结构式作为参考:
PD-0184264的结构式
CI-1040的结构式
2-(2-氯-4-碘苯基氨基)-N-(环丙基甲氧基)-3,4-二氟苯甲酰胺
本文所用的“代谢物”是指所述MEK抑制剂代谢的中间终产物,其在受试者降解所述MEK抑制剂期间,例如在肝脏中出现。在优选的实施方案中,所述MEK抑制剂是CI-1040的代谢物,例如PD0184264是所述MEK抑制剂CI-1040的代谢物。
为了本发明的目的,如上定义的MEK抑制剂还包括其药学上可接受的盐。本文所用的短语“药学上或美容上可接受的盐”是指那些对于所需给药形式安全且有效的本发明的化合物的盐。药学上可接受的盐包括与阴离子,例如衍生自盐酸、磷酸、乙酸、草酸、酒石酸等形成的盐,以及与阳离子,例如衍生自钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙基氨基乙醇、组氨酸、普鲁卡因等形成的盐。
如上所述,汉坦病毒感染是全世界的公共健康问题。目前,还没有WHO或FDA批准的靶向汉坦病毒的疫苗或抗病毒药物。然而,在治疗流感方面,本发明人较早地证明了MEK抑制剂,诸如CI-1040和PD0184264(ATR002)(CI-1040的活性代谢物)在体外和体内水平上抗流感病毒的抗病毒潜力。以下结果表明,体外实验显示以40μM CI-1040或40μM ATR-002处理Vero细胞可以成功降低汉坦病毒的繁殖。在实施例1中,观察到与溶剂对照组相比较病毒滴度下降>90%,参见图1和2。另外,体内实验表明,与仅用溶剂处理的动物相比较,以75mg/Kg/天的ATR-002处理小鼠5天会导致病毒滴度完全降低,如实施例2和图3和4中所述。
尽管汉坦病毒在细胞质中复制且不知道其具有核相,但是通过用MEK抑制剂ATR-002或CI-1040抑制Raf/MEK/ERK通路成功削弱了PUUV的繁殖。
通过施用本发明的MEK抑制剂来预防或治疗的病毒感染是由汉坦病毒引起的感染。已知的汉坦病毒包括普马拉病毒、辛诺柏病毒、汉城病毒、汉坦病毒(Hantaan virus)、多布拉瓦-贝尔格莱德病毒(Dobrava-Belgrad virus)、萨列马岛病毒(Saaremaa virus)和安第斯病毒(Andes virus)。
如上所述,汉坦病毒感染本身存在两种临床表现。第一种是汉坦病毒肾综合征出血热(HFRS),其中死亡率是12%;第二种是汉坦病毒肺综合征(HPS),其中死亡率是40%。疾病的严重程度取决于致病的汉坦病毒种类和病毒载量。例如,已知该病的严重病程是由汉坦病毒、多布拉瓦-贝尔格莱德病毒、辛诺柏病毒和安第斯病毒引起的,而该病的中度病程更可能是例如普马拉病毒或萨列马岛病毒引起的。
汉坦病毒肾综合征出血热(HFRS)也被称为韩国出血热、流行性出血热和流行性肾病。引起HFRS的种类包括汉坦正汉坦病毒、多布拉瓦-贝尔格莱德正汉坦病毒、萨列马岛病毒、汉城正汉坦病毒、普马拉正汉坦病毒和其他欧亚正汉坦病毒。HFRS的症状通常在暴露于感染性物质后1至2周内发展,但在罕见的情况下,可能需要长达8周才能发展。最初的症状是突然开始,包括剧烈头痛、背部和腹部疼痛、发烧、发冷、恶心和视力模糊。个体可能具有面部潮红、眼睛发炎或发红、或皮疹。后期症状可包括低血压、急性休克、血管渗漏和急性肾功能衰竭,这些均会导致严重的体液超负荷。
疾病的严重程度根据引起感染的病毒而变化。汉坦和多布拉瓦病毒感染通常引起严重的症状,而汉城、萨列马岛和普马拉病毒感染通常更为温和。
该综合征也可能致命。在一些情况下,已知其会造成永久性肾衰竭。HFRS仅通过临床诊断难以诊断,往往需要血清学证据。lgG抗体滴度在1周内上升四倍,抗汉坦病毒抗体lgM类型的存在是急性汉坦病毒感染的良好证据。患有急性发热性流感样疾病、不明来源的肾衰竭、有时还有肝功能异常的患者,均应怀疑患有HFRS。
汉坦病毒肺综合征(HPS)通常由美国种汉坦病毒引起。这些病毒包括黑溪运河病毒(BCCV)、纽约正汉坦病毒(NYV)、莫农加希拉病毒(MGLV)、辛诺柏正汉坦病毒(SNV)和原产于美国和加拿大的汉坦病毒属的某些其他成员。特定啮齿动物是汉坦病毒的主要宿主,包括佛罗里达南部的刚毛棉鼠(Sigmodon hispidus),其是黑溪运河病毒的主要宿主,加拿大和美国西部的鹿鼠(Peromyscus maniculatus),其是辛诺柏病毒的主要宿主,以及美国东部的白脚小鼠(Peromyscus leucopus),其是纽约病毒的主要宿主。在南美洲,长尾小啸鼠和小啸鼠属的其他物种被证明是安第斯病毒的宿主。
HPS的症状是流感样症状,如发热、咳嗽、肌痛、头痛、嗜睡以及呼吸短促,这些症状会迅速恶化为急性呼吸衰竭。其特征在于呼吸短促突然发作,并迅速发展为肺水肿;尽管机械通气和强效利尿剂干预,但它通常是致命的。致死率为36%。HPS容易被忽略,这是因为其早期症状与流感非常相似。感染的患者在接触后几周内会出现疲劳、发热和肌肉疼痛,通常伴有头痛、头晕和胃肠道问题。在最初症状消退后约一周,开始疾病的第二阶段,由于肺部充满液体,患者经历严重的咳嗽和呼吸短促。在HPS的后期,肺被严重损伤,导致高病死率。
在本发明治疗或预防的用途中,所述患者优选是哺乳动物,在优选的实施方案中,是灵长类动物,最优选是人类患者。在一种替代的给药方式中,计划治疗已知是汉坦病毒携带者的哺乳动物,例如啮齿类动物和蝙蝠,特别是大鼠、小鼠和鹿小鼠,以预防人类经由这些宿主的感染。在本文中,在汉坦病毒感染率高的地区,可以考虑经由吸入(环境喷雾制剂)的广谱给药方式。由于在汉坦病毒感染中人对人的传播是罕见的,因此对哺乳动物非人类宿主如啮齿动物的此种广泛应用可作为预防措施。
此外,向已经与啮齿动物或啮齿动物排泄物接触或一直在汉坦病毒爆发常见区域生活或旅行的人类受试者施用MEK抑制剂以预防汉坦病毒感染可能是有用的,尤其是人类受试者一直在已知有导致HFRS或HPS的汉坦病毒感染的区域生活或旅行的情况下。
具体地,当人类患者一直在韩国、塞尔维亚或美国的已知由美国黑溪运河病毒(BCCV)、纽约正汉坦病毒(NYV)、莫农加希拉病毒(MGLV)、辛诺柏正汉坦病毒(SNV)或安第斯病毒引起的汉坦或多布拉伐病毒感染或汉坦病毒感染的区域旅行或生活时,此种治疗或预防性治疗是有用的。由于汉坦病毒的传播主要通过雾化的啮齿动物排泄物(尿、唾液、粪便)发生,因此在接触啮齿动物排泄物后立即开始预防性治疗,直至接触后10天没有感染症状。
所述MEK抑制剂可以口服、静脉内、胸膜内、肌内、局部或经由吸入给药。优选地,所述MEK抑制剂经由吸入或口服给药。
此外,在观察到HFRS或HPS的第一症状或人类患者与啮齿动物的排泄物接触后,可以在高达12小时、高达24小时、高达48小时、高达72小时或4至10天之间施用所述MEK抑制剂。
在本发明治疗或预防的用途的一个实施方案中,所述化合物MEK抑制剂可以有效治疗剂量口服或经由吸入施用。在一个实施方案中,所述MEK抑制剂的治疗有效量是例如0.1mg至2000mg、0.1mg至1000mg、0.1至500mg、0.1至200mg、30至300mg、0.1至75mg、0.1至30mg。
如上所述,本发明进一步提供包含MEK抑制剂或其药学上可接受的盐或代谢物的药物组合物,该药物组合物用作预防和/或治疗病毒感染,优选由汉坦病毒引起的感染的药物。
本发明的药物组合物可以是如下形式:口服给药的悬浮液或片剂;鼻腔喷雾剂、例如作为无菌可注射水性或油性混悬液或栓剂的无菌注射制剂(静脉内、胸膜内、肌内)。当以悬浮液口服给药时,这些组合物根据药物制剂领域可用的技术制备,可以含有用于提供体积的微晶纤维素、作为悬浮剂的藻酸或藻酸钠、作为增粘剂的甲基纤维素和本领域已知的甜味剂/调味剂。作为速释片剂,这些组合物可以含有微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和乳糖和/或本领域已知的其它赋形剂、粘合剂、填充剂、崩解剂、稀释剂和润滑剂。注射溶液或混悬液可以根据已知技术使用以下物质来配制:合适的无毒、肠胃外可接受的稀释剂或溶剂,例如甘露醇、1,3-丁二醇、水、林格氏溶液或等渗氯化钠溶液;或合适的分散剂或润湿剂和助悬剂,例如包括合成的单-或二甘油酯的无菌、温和、固定油;以及包括油酸的脂肪酸。本发明方法中的药物化合物可以以任何合适的单剂型给药。在本发明的药物组合物的上下文中,合适的口服制剂也可以是片剂、胶囊、悬浮液、糖浆、口香糖、糯米纸囊剂、酏剂等形式。药学上可接受的载体,例如粘合剂、赋形剂、润滑剂和甜味剂或调味剂可以包括在口服药物组合物中。如果需要,也可以包括用于改变味道、颜色和特殊形式的形状的常规试剂。
对于可注射制剂,药物组合物可以是在合适的小瓶或管中与合适的赋形剂混合的冻干粉末。在临床使用前,药物可通过将冻干粉末溶解在合适的溶剂系统中而重构,以形成适于静脉内或肌内注射的组合物。
在一个实施方案中,药物组合物可以是含有治疗有效量(例如,0.1mg至2000mg,0.1mg至1000mg,0.1至500mg,0.1至200mg,30至300mg,0.1至75mg,0.1至30mg)的MEK抑制剂的口服给药形式(例如,片剂或胶囊或糖浆等)。
定义
在整个说明书和随后的权利要求书中,除非上下文另有要求,词语“包括(comprise)”及其变体如“包括(comprise)”和“包括(comprising)”应理解为意指包括所述的整体或步骤或整体或步骤的组,但不排除任何其它整体或步骤或整体或步骤的组。当在本文中使用时,术语“包括(comprising)”可以用术语“含有(containing)”替换,或者有时当在本文中使用时用术语“具有(having)”替换。
当在本文中使用时,“由…组成”排除了未在在权利要求部分(claim element)中指定的任何元素、步骤或成分。当在本文中使用时,“基本上由…组成”未排除对权利要求的基本特征和新颖性特征没有实质影响的材料或步骤。在本文的各实施方式中,“包括(comprising)”、“基本上由…组成”和“由…组成”中的任何一个可用另外两个术语中的一个替换。
如本文所用,将多个列举的元素(elements)之间的连词“和/或”理解为既包含个体也包含组合选项。例如,如果用“和/或”连接两个元素,第一种选项是指仅第一个元素适用而第二个元素不适用;第二种选项是指仅第二个元素适用而第一个元素不适用;第三种选项是指第一个元素和第二个元素一起适用。这些选项中的任一情况都可以理解为落入该含义中,因此满足本文使用的术语“和/或”的要求。同时适用多个选项也可以理解为落入该含义中,因此满足本文使用的术语“和/或”的要求。
实施例
材料
普马拉病毒(PUUV)株Sotkamo
-欧洲的主要汉坦病毒
-可在S2实验室处理
Vero细胞系
-来自非洲绿猴肾细胞的细胞系
-常用于病毒生长
-I型干扰素缺乏
细胞培养基:
基础培养基:IMDM,1%P/S,1%L-Gln,10%FCS
ATR-002/CI-1040处理培养基:基础培养基w/o FCS
病毒感染培养基:基础培养基w/o FCS
MEK抑制剂ATR-002(PD0184264)[2-(2-氯-4-碘苯基氨基)-N-3,4-二氟苯甲酸,CI-1040的活性代谢物,在ChemCon GmbH(德国,弗莱堡)合成。
MEK抑制剂CI-1040[2-(2-氯-4-碘苯基氨基)-N-(环丙基甲氧基)-3,4-二氟苯甲酰胺]在ChemCon GmbH(德国,弗莱堡)合成。
实施例1:病毒产量减少测试
方法:
将Vero细胞接种于24孔板中(1×106细胞/孔),在37℃、5%CO2下孵育。
接种后一天,以PUU-病毒颗粒(MOI 0.3)感染细胞。
感染后1h,用40μM Cl-1040、40μM ATR-002或DMSO(溶剂对照)处理细胞。
感染后72h收集上清液,经由以下的TCID50试验确定病毒滴度。
TCID50试验(SOP-ATR-0119)
使用标准操作程序SOP-ATR-0119进行病毒滴定。简而言之,将来自VYR试验的肺和肾/上清液的10%匀浆物以1:10的系列稀释液进行稀释。用不同的10倍病毒稀释液感染Vero细胞,在37℃下在5%CO2气氛中孵育60分钟。孵育后,用PBS漂洗细胞,并补充200μlIMDM(Iscove's Modified Dulbecco's培养基)/BA(牛白蛋白)-培养基(0.2%BA,1mMMgCl2,0.9mM CaCl2,100U/ml青霉素,0.1mg/ml链霉素),在37℃下在5%CO2中孵育7天。此后,洗涤Vero细胞,在4℃用-Histofix固定30分钟。用PBS洗涤后,用Triton-X-100和FCS使细胞渗透化。孵育初级抗体(抗PUUV-NP-AB)一小时。洗涤后,将二级抗体施用于细胞30分钟。然后,洗涤细胞并用底物TrueBlue染色10分钟。通过光学显微镜进行分析。
结果:
从图1可以看出,在CI-1040的存在下,与溶剂对照组相比较,实现了>2log10-步的显著病毒滴度降低。这相当于病毒滴度降低>99%。
在图2中看到了类似的结果,在ATR-002的存在下,与溶剂对照组相比较,实现了>1,5log10-步的病毒滴度降低。这相当于病毒滴度降低>90%。
结论:
用40μM CI-1040或40μM ATR-002处理以PUUV(MOI 0.3)感染的Vero细胞造成与溶剂对照相比病毒滴度的强烈降低。
抑制Raf/MEK/ERK-通路损害了普马拉病毒的体外繁殖。
实施例2:ATR-002在体内抗汉坦病毒的抗病毒作用
材料和方法
小鼠
目前还没有可靠的建立的研究汉坦病毒感染的动物模型。I型干扰素缺乏的Vero细胞被证明是一种良好的体外模型,但是没有I型干扰素缺乏的小鼠可用。因此,选择干扰素受体敲除小鼠(IFNα/β/γR-/-(AG129)小鼠)用于体内研究。AG129小鼠用于以下实验。
方法
AG129小鼠鼻内感染PUUV(50μl PBS中5×105/pfu,每个鼻孔接种25μl)。
用75mg/Kg/天的ATR-002(在DMSO/Cremophor EL/PBS中)处理,感染后5h开始,连续5天。给药途径:灌胃口服,37.5mg/kg,每天两次(9am和6pm)。对照组相应地仅用溶剂处理。
在感染后第7天和第10天处死小鼠,以确定肺和肾中的病毒滴度(TCID50测试)。
结果
在PUUV感染后,没有动物体重下降、出现临床症状或死亡。
在感染后7天和10天,在肺和肾的溶剂对照动物中可检测到PUUV。在第10天病毒滴度更高。
在用75mg/kg/天的ATR-002处理的动物肺和肾中,在感染后7天和10天没有检测到病毒(检出限:肺:3.4log10(TCID50/g器官)肾:3.2log10(TCID50/g器官)),分别如图3和4所示。
病毒量的减少(用溶剂对照和用ATR-002处理的匀浆物之间的比较)非常显著(双向-ANOVA,P<0.0001)。
结论
研究表明,PUUV感染后5小时开始,用75mg/Kg/天的ATR-002(在DMSO/CremophorEL/PBS中)处理小鼠五天显著降低了肺和肾的病毒量。
Claims (12)
1.用于治疗或预防哺乳动物中汉坦病毒感染的MEK抑制剂。
2.根据权利要求1供使用的所述MEK抑制剂,其中所述MEK抑制剂选自CI-1040、PD-0184264、GSK-1120212、GDC-0973、PLX-4032、AZD6244、AZD8330、AS-703026、RDEA-119、RO-5126766、RO-4987655、PD-0325901、TAK-733、AS703026、PD98059和PD184352或其药学上可接受的盐或代谢物。
3.根据权利要求2所述的供使用的MEK抑制剂,其中所述MEK抑制剂是CI-1040或PD-0184264。
4.根据权利要求1至3中任一项所述的供使用的MEK抑制剂,其中所述哺乳动物是啮齿动物或人。
5.根据权利要求4所述的供使用的MEK抑制剂,其中所述哺乳动物是人,所述人表现出汉坦病毒肾综合征出血热(HFRS)或汉坦病毒肺综合征(HPS)的症状。
6.根据权利要求5所述的供使用的MEK抑制剂,其中在观察到HFRS或HPS的第一症状后高达12小时、高达24小时、高达48小时、高达72小时或4至10天之间施用所述MEK抑制剂。
7.根据权利要求1至6中任一项所述的供使用的MEK抑制剂,其中向已经与啮齿动物或啮齿动物排泄物接触或处于汉坦病毒爆发普遍的区域中的人类受试者施用所述MEK抑制剂用于预防汉坦病毒感染。
8.根据权利要求4至7中任一项所述的供使用的MEK抑制剂,其中所述人类受试者在已知存在导致HFRS或HPS的汉坦病毒感染的区域中一直生活或旅行。
9.根据权利要求8所述的供使用的MEK抑制剂,其中所述汉坦病毒是由美洲物种如黑克里克管病毒(BCCV)、纽约正汉坦病毒(NYV)、单门哈拉病毒(MGLV)、诺伯斯正汉坦病毒(SNV)或安德斯病毒引起的汉坦或东巴拉夫病毒感染,或者汉坦病毒感染。
10.根据权利要求1至9中任一项所述的供使用的MEK抑制剂,其中所述MEK抑制剂口服给药或经由吸入给药。
11.根据权利要求4所述的供使用的MEK抑制剂,其中所述哺乳动物是啮齿动物,所述MEK抑制剂施用于啮齿动物群体以预防与所述啮齿动物接触的人感染。
12.根据权利要求11所述的供使用的MEK抑制剂,其中所述MEK抑制剂通过吸入给药。
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WO2019076947A1 (en) * | 2017-10-17 | 2019-04-25 | Atriva Therapeutics Gmbh | NEW MEK INHIBITOR FOR THE TREATMENT OF VIRAL AND BACTERIAL INFECTIONS |
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