CN106551939A - 一种促进单纯疱疹病毒复制的化合物及应用 - Google Patents
一种促进单纯疱疹病毒复制的化合物及应用 Download PDFInfo
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Abstract
本发明属生物制药技术领域,涉及一种促进单纯疱疹病毒复制的化合物和应用。本发明发现9种已知化合物能够促进HSV复制过程,包括JQ‑1(PubChem CID 46907787),PFI‑1(PubChem CID 71271629),I‑BET‑762(PubChem CID 46943432),TG101348(PubChem CID 16722836),Quisinostat(PubChem CID 11538455),CUDC‑907(PubChem CID 54575456),CUDC‑101(PubChem CID 24756910),Givinostat(PubChem CID 9804992),HDAC‑42(PubChem CID 6918848)。这些化合物能不同程度地增加病毒感染,可分类为去乙酰化酶抑制剂(HDACi)或BET溴域蛋白,如BRD4蛋白(Genbank accession NP_490597)溴域(bromodomain proteins)抑制剂。它们是具有单独杀伤肿瘤能力的药物,也能与HSV溶瘤病毒联合应用于肿瘤治疗和研究。
Description
技术领域
本发明属于生物制药技术领域,具体涉及一种促进单纯疱疹病毒复制的化合物及应用。
背景技术
人单纯疱疹病毒(human herpes simplex virus,HSV)包括HSV-1和HSV-2,是引起人类疾病的主要病原体。HSV-1感染主要引起口龈炎、咽炎、疱疹性角膜炎、皮肤疱疹性湿疹等,全球约2/3的成年人感染过该病毒。HSV-2感染是一种性传播疾病(STD),10%以上性活跃期人群感染该病毒。作为STD病原体之一的HSV-2,其感染还能显著增加HIV的传播。治疗HSV感染的药物主要是核苷酸衍生物,具有一定疗效。
单纯疱疹病毒感染的最大特点包括溶细胞感染和潜伏感染两种形式。病人一旦感染HSV,病毒可以巡神经系统迁移,并在神经节潜伏。潜伏过程中,没有明显病毒基因复制和病毒颗粒形成,但是潜伏感染的病毒可以再激活,是造成反复感染的主要原因。我们对于病毒再激活机制缺乏了解,但是机体免疫力低下、疲劳或外界压力以及环境因素比如强紫外线照射等都可以再激活潜伏状态的病毒,使其进入复制感染状态,导致再感染。因此,了解病毒复制、潜伏感染以及再激活机理对于根除单纯疱疹病毒感染具有实际意义。
HSV感染宿主细胞的过程包括病毒的吸附、侵入、脱壳、生物大分子复制和转录、病毒颗粒组装以及病毒颗粒的释放,整个生活周期约20小时。其中,病毒吸附、生物大分子合成过程都是治疗和预防HSV感染的靶点。
HSV基因组长约150kb,病毒编码蛋白严格按照时间空间顺序进行,并以此分为即刻早期蛋白、早期蛋白和晚期蛋白。即刻早期蛋白的表达能保证早期蛋白的顺利表达,早期蛋白又为病毒的DNA复制和晚期蛋白的表达提供服务。根据报道,HSV的VP16蛋白和即刻早期蛋白ICP0基因启动子区具有核转录因子NF-κB的结合位点,NF-κB的结合可以帮助这些蛋白的表达,而这两个蛋白在病毒即刻早期、早期以及晚期基因的表达过程中具有重要作用。有文献报道抑制NF-κB活化相关通路,能显著阻断HSV的复制。另外,HSV入侵细胞后,其基因组伴有组蛋白修饰,包括乙酰化和甲基化等,这些修饰可能与HSV两种感染形式以及再激活过程有关。Danaher等报道,组蛋白去乙酰化酶的抑制剂曲古抑菌素A(trichostatin A,TSA)以及丁酸钠(sodium butyrate)等能够促进潜伏的HSV-1在神经元细胞中重新激活发生裂解性感染。另外,诱导宿主细胞凋亡过程也能激活潜伏的HSV-1病毒。研究表观遗传因素在HSV病毒感染中的作用,不但可以揭示HSV复制机理,还可以发现作用于HSV潜伏感染和再激活过程的药物。
单纯疱疹病毒是人类最常见的病原体,其感染具有宿主专一性。继2015年美国FDA批准携带细胞因子GM-CSF的HSV载体用于黑色素瘤治疗后,具有溶瘤能力的HSV正在广泛用于肿瘤临床治疗实验。
发明内容
本发明需要解决的问题是提供一种促进单纯疱疹病毒复制的化合物及应用,本发明以小分子化合物干扰病毒基因转录过程而影响HSV复制周期和感染,小分子化合物可以促进病毒复制,能够用于HSV介导的肿瘤治疗,激活潜伏感染的HSV。
本发明通过筛选小分子化合物库,发现至少9种已知化合物能够促进HSV复制过程,包括JQ-1(PubChem CID 46907787)结构式为PFI-1(PubChem CID71271629)结构式为I-BET-762(PubChem CID 46943432)结构式为TG101348(PubChem CID 16722836)结构式为Quisinostat(PubChem CID 11538455)结构式为CUDC-907(PubChemCID 54575456)结构式为CUDC-101(PubChem CID 24756910)结构式为Giv inostat(PubChem CID 9804992)结构式为HDAC-42(PubChem CID 6918848)结构式为本发明所述以其中一种化合物提前预处理或处理感染中的样本,不同时间跟踪、检查病毒产率、病毒基因产物以及病毒介导的报告基因传递效率,这些化合物均能不同程度地增加病毒感染。进一步研究发现这些化合物可以分类为去乙酰化酶抑制剂(HDACi)和BET溴域蛋白比如BRD4蛋白(Genbank accession NP_490597)溴域(bromodomain proteins)抑制剂。溴域抑制剂JQ-1等主要促进转录复合物向病毒基因启动子区集聚,使转录延伸因子专注于病毒基因转录延伸,增加病毒复制速率和效率。
本发明的有益效果是:
1.本发明所述化合物可以促进病毒复制,能联合溶瘤性HSV用于肿瘤治疗;
2.本发明所述化合物可以激活潜伏感染的HSV,能与抗HSV药物或中和抗体合用,清除潜伏感染的HSV;
3.本发明所述化合物作用机制清楚,可作为结构优化的先导化合物;
4.本发明所述化合物正在作为抗肿瘤药物开发,制备成治疗肿瘤的药物。
本发明所述的化合物可以是具有单独杀伤肿瘤的能力药物,也可以与HSV溶瘤病毒联合应用于肿瘤治疗和研究。
附图说明
图1.代表化合物JQ-1、PFI-1、I-BET-762(I-BET)和TG101348(TG)促进HSV-1和HSV-2复制
A.猴肾Vero细胞首先处理JQ-1(JQ1,300nM),PFI-1(500nM),I-BET-762(I-BET,1μM),TG101348(TG,3μM)2小时,然后以MOI=1分别感染。36小时后收集样品,测定病毒滴度。Trichostatin A(TSA)是组蛋白去乙酰化酶抑制剂,文献报道具有促进HSV-1和HSV-2复制能力,实验中以TSA 150nM处理作为阳性对照。
B.代表化合物JQ-1(JQ1)、PFI-1对病毒空斑形成影响。病毒空斑在JQ1(300nM)和PFI-1(500nM)处理的样品中显著大于溶剂处理的对照。
C.代表化合物JQ-1在不同来源的细胞均能促进HSV-1和HSV-2复制。
*:p<0.05;**:p<0.01.
图2.代表化合物JQ-1促进HSV-1和HSV-2感染的剂量以及加样时间曲线。
A.以不同剂量JQ-1处理HeLa细胞,然后感染1MOI HSV-1或HSV-2.感染36小时后收集样品,滴定病毒。
B.用JQ-1在不同时间处理HSV-1或者HSV-2感染或者感染之前处理HeLa细胞,36小时后滴定病毒。对照实验显示以JQ-1直接处理病毒(Tx-V)不影响病毒感染。
C.JQ-1对病毒复制周期的影响。以JQ1(300nM)处理HeLa细胞,并同时感染HSV-1(MOI=0.3).不同时间取样,滴定病毒。
图3.JQ-1可以促进携带GFP报告基因的HSV-1(HSV-1/EGF)感染效率。
以HSV-1/GFP感染HeLa细胞(MOI=0.3和1.0)。以100nM和300nM JQ-1或无活性的(-)JQ-1对照处理细胞。36小时后测定平均荧光强度(MFI)。
图4.实施实例三JQ-1能够激活潜伏HSV-1。
被HSV-1潜伏感染的小鼠三叉神经节,以含有300和1000nM JQ-1培养基或对照培养基培养,24和36小时后匀浆,在Vero细胞滴定病毒滴度。
图5.JQ-1处理能够导致BRD4向病毒基因启动子区集聚。
A. HSV-1复制需要BRD4与转录正性延伸因子(P-TEFb)复合物。
B. JQ-1促进感染所需的BRD4与P-TEFb复合物形成。
C. JQ-1促进感染所需的BRD4/P-TEFb复合物集聚于病毒基因启动子区。
具体实施方式
下述实施例中所使用的试验方法如无特殊说明,均为常规方法。下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径获得。
非洲绿猴肾细胞Vero细胞、SK-N-SH细胞购于上海中科院细胞库,Balb/C小鼠胚胎成纤维细胞系实验室按常规方法制备。人源HeLa细胞、HEp-2细胞以及单纯疱疹病毒HSV-2(Indiana株)购自美国典型培养物保藏中心(ATCC),HSV-1系中国科学院昆明动物所李奇涵研究员惠赠,携带GFP报告基因的HSV-1-GFP购自北京五加和公司。表观遗传小分子化合物库购自Selleck公司(上海)。
实施例一 表观遗传小分子化合物促进HSV-1和HSV-2感染实验
(一)小分子化合物库筛选
于感染前一天在96孔板中培养Vero细胞,每孔3x103细胞。含有129个化合物的小分子库以低于其细胞毒性(IC50)3倍的浓度为最大筛选浓度(比如产品说明标注A化合物IC50为300nM,则起始最高浓度设为100nM),以DMEM培养基为稀释体系,3-倍稀释出5个浓度(以A化合物为例,试验浓度则为100,33.3,11.1,3.7和1.2nM),在感染之前两个小时处理Vero细胞,三孔重复。同时设置无药物处理的正常对照组和化合物毒性对照(以最大试验浓度100nM为样本)。以HSV-1或HSV-2感染细胞,感染剂量为每个细胞1个成空斑病毒(MOI=1)。于37℃,5%湿度CO2培养箱中培养,用显微镜直接观察病毒感染引起的宿主细胞形态改变,细胞变圆,脱落破碎等细胞病变效应(CPE)。培养72小时之后,采用经典的检测细胞活力的MTT方法测定Vero细胞活性。
具体地说,加入终浓度为0.5mg/mL的MTT培养细胞4小时之后,由于正常的活细胞能将MTT还原成水不溶性的蓝紫色结晶甲瓒并沉积在细胞中,所以通过去除培养上清后,加入100μL DMSO将甲瓒溶解,用酶标仪在570nm处测定吸光值(OD),将各组细胞的吸光值减去吸光本底值后,通过处理组细胞的吸光值与正常对照组细胞的吸光值相比。单纯疱疹病毒感染可以导致细胞死亡或活力下降,因此可以用以判定化合物对病毒感染的抑制(OD读数上升)或促进(OD读数下降)病毒复制。根据公式(处理组吸光值-未处理感染组吸光值)/(正常对照组吸光值-未处理感染组吸光值)x 100%,计算药物对病毒感染的影响,以及判断化合物对细胞生长的影响。如果一个化合物没有明显的细胞毒性,低比值则说明病毒感染对细胞影响加剧。结合显微镜观察结果,可以初步判定某化合物是不是具有促进病毒感染的能力。
我们以吸光值变化20%为判定点,得出某个化合物对病毒感染具有增加或抑制作用的结论。验证试验则以该值为参考,得出某化合物导致OD读数值降低20%的浓度,设为EC20,用以定量比对化合物活性。筛选结果见表1.
文献已有HDAC抑制剂trichostatin A促进单纯疱疹病毒复制的报道,但是HAD抑制剂Quisinostat(11538455),CUDC-907(54575456),CUDC-101(24756910),Givinostat(9804992),HDAC-42(6918848)以及溴域蛋白抑制剂JQ-1,PFI-1,I-BET-762以及TG101348促单纯疱疹病毒感染系首次发现。
(二)溴域蛋白抑制剂代表化合物JQ-1、PFI-1、I-BET-762(I-BET)和TG101348(TG)促进HSV-1和HSV-2复制
猴肾Vero细胞于96孔板中培养过夜。用JQ-1(JQ1,300nM),PFI-1(500nM),I-BET-762(I-BET,1μM),TG101348(TG,3μM)处理2小时,然后以HSV-1或HSV-2分别感染细胞(MOI=1),复孔。36小时后收集样品,在Vero细胞上测定病毒滴度。Trichostatin A(TSA)是组蛋白去乙酰化酶抑制剂,文献报道具有促进HSV-1和HSV-2复制能力,实验中以TSA 150nM处理作为阳性对照。
在平行实验中,Vero细胞于6孔板中培养过夜,化合物处理、感染的细胞,72小时以后以多聚甲醛固定,以结晶紫染色。干燥以后在显微镜下照相,用ImageJ统计空斑大小,作图比较代表化合物对空斑形成的影响。JQ1(300nM)和PFI-1(500nM)处理的样品中空斑面积变大显著大于溶剂处理的对照。
(三)代表化合物在不同来源的细胞中都有促进病毒感染
为了检验代表化合物是不是在人源以及其它细胞中具有促进单纯疱疹病毒感染的能力,我们在HeLa,HEp-2,SH-N-SK以及小鼠胚胎成纤维细胞(MEF)上检验这些化合物促进单纯疱疹病毒感染的能力。
细胞于96孔板中培养过夜,用指定浓度的样品处理细胞2小时,分别感染HSV-1或HSV-2,每个处理组设置三个复孔,同时设置无药物处理不感染的正常对照组以及无药物处理的感染组,36小时后收集样品,检查病毒滴度。结果表明,JQ-1,PFI-1等在人肿瘤细胞上也有促进病毒复制的能力。
由于JQ-1效果在绿猴肾Vero细胞以及人HeLa细胞中表现了类似效果,考虑到单纯疱疹病毒载体在人肿瘤治疗中的广泛应用,我们交替使用人源肿瘤HeLa细胞以及病毒学实验中常用的Vero细胞进行后续实验。
实施例二 化合物JQ-1促单纯疱疹病毒感染浓度以及时间曲线测定
(一)浓度及加药时间测定
根据以上测定的EC20数据,我们选取JQ-1为代表,在病毒感染前2小时以50,100,300和500nM JQ-1处理Vero细胞,然后以1MOI病毒感染并行未处理对照。36小时后收集样品,滴定病毒。结果显示,JQ-1在上述浓度下都可以促进HSV-1和HSV-2感染。
另外,我们还以类似的方法,在病毒感染前2小时(-2)、感染的同时(0)、以及添加病毒后的1、3、6、12和24小时添加JQ-1(300nM),感染36小时后收集细胞样品,以二次感染滴定病毒滴度。在感染之前或者感染的前6个小时添加化合物,都能明显促进病毒复制,在12小时添加效果开始变弱,而24小时添加效果不明显。另外,我们还证明JQ-1促进单纯疱疹病毒感染不是通过直接作用于病毒颗粒。为了达到此目的,我们将终浓度为300nM的JQ-1与30倍的HSV-1或者HSV-2于100μl无血清培养基中混合,37℃中孵育60min后,取混合液10μl感染24孔板的Vero细胞,重复3个复孔,同时设置无处理的正常病毒组和培养基处理的病毒组用以检验JQ-1直接处理病毒对病毒复制的影响。我们发现JQ-1直接处理病毒对其复制没有明显影响。由于体外处理的病毒时添加的JQ-1被30倍稀释,所以JQ-1的终浓度为对单纯疱疹病毒复制无影响的10nM。因此,JQ-1促单纯疱疹病毒复制应该是作用于病毒细胞入侵或者是病毒进入细胞之后的过程。
(二)代表性化合物JQ-1对单纯疱疹病毒HSV-1复制周期的影响
HeLa细胞于96孔板中培养过夜。用JQ-1(JQ1,300nM)处理2小时,然后以HSV-1感染细胞(MOI=0.3),复孔。感染不同时间收集样品,病毒滴度在Vero细胞上滴定。结果显示JQ-1处理的样品在感染后12、24和36小时的病毒滴度都明显地高于对照处理的样品。
实施例三 JQ-1促进携带GFP报告基因的HSV-1(HSV-1/EGF)感染效率。
HeLa细胞于6孔板中培养过夜。用JQ-1(JQ1,300nM)或无溴域蛋白抑制活性的(-)JQ-1为对照处理细胞2小时,然后以HSV-1/GFP感染细胞(MOI=0.3和1.0),复孔。感染36小时后收集样品,以流式细胞方法(FACS)检测GFP荧光强度,统计平均荧光强度(MFI)作为JQ-1对HSV-1携带基因表达的作用。结果表明JQ-1,而非无溴域抑制活性的(-)JQ-1能够促进HSV-1携带报告基因的表达。
实施例四 JQ-1能够激活潜伏HSV-1
5-7周雌性Balb/C小鼠15-20只,轻度麻醉,在生物安全柜内以注射器针头在角膜上轻轻地滑动5-6次,然后以移液器在划痕处滴注2μL含有HSV-1病毒的液体(共计1x106PFU),将小鼠放回饲养笼,饲养约一个月,定期观察小鼠眼角膜感染进程。
按文献报道方法,摘取小鼠三叉神经节,置于含DMEM的6孔板中,添加300和1000nMJQ-1或相应对照化合物,每组3对,培养从24和36小时,然后收取样本,液氮速冻,保存于-80℃冰箱备用。
将三叉神经于200μL DMEM培养基中匀浆,5000xg离心5分钟,匀浆液倍比稀释,以病毒空斑实验鉴定病毒滴度,用以判断JQ-1等化合物对潜伏感染HSV-1再激活影响。结果显示300和1000nM JQ-1处理的样品中HSV-1滴度明显高于未处理或者(-)JQ-1对照处理的样品,处理36小时样品中病毒平均滴度分别为1.3x104,2.7x104,1.3x103,2.3x103PFU/mL.
实施例五 JQ-1处理能够导致BRD4向病毒基因启动子区集聚。
HeLa细胞于6孔板中,感染或者不感染HSV-1病毒6和9小时小时。收集样品,以抗-BRD4抗体行免疫共沉淀分析,免疫印迹法分析沉淀物中转录延伸因子亚单位CDK9以及RNA聚合酶亚单位Rpb-1。结果显示,HSV-1感染样品中,CDK9和Rpb-1含量明显增加。
以同样方法,检查JQ-1处理样品中,BRD4与转录延伸调控蛋白结合情况。结果显示,500nM JQ-1处理的样品中,与BRD4结合的CDK9和Rpb-1明显多于感染但无药物处理的样品。
最后,进行性染色质-免疫共沉淀(ChIP)实验,以实时定量PCR(qPCR)方法检查与BRD4结合的HSV-1基因启动子,包括ICP0,ICP4,ICP8,ICP22以及gB基因启动子,发现JQ-1处理能够显著增加病毒启动子与BRD4的结合。这些结果表明JQ-1处理能够增加病毒复制所需的延伸因子和RNA聚合酶向病毒基因转录倾斜,从而促进HSV-1和HSV-2复制。
Claims (5)
1.一种促进单纯疱疹病毒复制的化合物,其结构式是
2.权利要求1所述促进单纯疱疹病毒复制的化合物在制备治疗肿瘤药物中的应用。
3.权利要求1所述促进单纯疱疹病毒复制的化合物与抗HSV药物或中和抗体合用,清除潜伏感染的HSV。
4.权利要求1所述促进单纯疱疹病毒复制的化合物能促进病毒复制,能联合溶瘤性HSV用于肿瘤治疗。
5.权利要求1所述促进单纯疱疹病毒复制的化合物用作分子探针揭示的BRD4蛋白结构域,用于改造单纯疱疹病毒和肿瘤治疗。
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CN107033147A (zh) * | 2017-04-25 | 2017-08-11 | 东南大学 | 一种bet/hdac双靶点抑制剂及其制备方法和应用 |
CN110101705A (zh) * | 2019-05-07 | 2019-08-09 | 河南农业大学 | Bet家族蛋白抑制剂的抗病毒用途 |
WO2020109389A1 (en) | 2018-11-28 | 2020-06-04 | Innovative Molecules Gmbh | Helicase primase inhibitors for treating cancer in a combination therapy with oncolytic viruses |
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YUJUN ZHAO等: "The Making of I‑BET762, a BET Bromodomain Inhibitor Now in Clinical Development", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Cited By (4)
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CN107033147A (zh) * | 2017-04-25 | 2017-08-11 | 东南大学 | 一种bet/hdac双靶点抑制剂及其制备方法和应用 |
WO2020109389A1 (en) | 2018-11-28 | 2020-06-04 | Innovative Molecules Gmbh | Helicase primase inhibitors for treating cancer in a combination therapy with oncolytic viruses |
CN110101705A (zh) * | 2019-05-07 | 2019-08-09 | 河南农业大学 | Bet家族蛋白抑制剂的抗病毒用途 |
CN110101705B (zh) * | 2019-05-07 | 2022-01-14 | 河南农业大学 | Bet家族蛋白抑制剂的抗病毒用途 |
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