CN111154755A - 一种双链寡核苷酸dna及其应用 - Google Patents
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Abstract
本发明公开了一种双链寡核苷酸DNA及其应用。所述的双链寡核苷酸DNA的正义链的核苷酸序列包含如序列表中SEQ ID NO.19所示的核苷酸序列，反义链的核苷酸序列包含如序列表中SEQ ID NO.20所示的核苷酸序列；所述的正义链和所述的反义链的长度均为30bp以上；或者，正义链的核苷酸序列如序列表中SEQ ID NO.3所示，反义链的核苷酸序列如序列表中SEQ ID NO.4所示；或者，正义链的核苷酸序列如序列表中SEQ ID NO.17所示，反义链的核苷酸序列如序列表中SEQ ID NO.18所示。本发明找到最短的DNA片段，使得将来产业化时合成容易，降低成本。
Description
技术领域
本发明属于生物医药领域，具体涉及一种双链寡核苷酸DNA及其应用。
背景技术
STING信号通路在先天免疫中的发现及其在肿瘤学中的潜在意义，使STING成为最小分子免疫肿瘤学靶标。几乎所有的大小制药公司都在竞争最有效和最具选择性的STING配体的制备，并试图在临床试验中证明其在缩小肿瘤方面的有效性。但是，STING是细胞内分子，无法通过抗体评估。它的天然配体cGAMP是环状二核苷酸结构，极易溶于水，但不稳定且在细胞外会迅速降解。大部分制药企业都致力于创造既保留两亲性结构，又结构稳定并具有细胞渗透性的配体衍生物。尽管具有极大的挑战性，但一些大型制药公司(诺华、默克和葛兰素史克)已通过各种肿瘤模型中肿瘤的缩小报道了STING的小分子配体衍生物及其在体内的活性。
但是，所有天然STING配体都属于可能涉及多个关键信号途径的次要信息。到目前为止，这是使用配体衍生物靶向STING的最具挑战性的问题。所有报道的小分子化合物的体内功效研究都是使用IT(肿瘤内)注射作为可行的药物传递途径，这将限制其临床应用。有两篇报道尝试将天然STING配体包装到脂质纳米颗粒中，并通过在小鼠模型中进行静脉注射成功进行了全身性递送。由于这些纳米颗粒仍然没有靶向机制，因此大剂量次级信息传递的最终安全性，仍有待于在灵长类动物中进行观察。
发明内容
本发明所要解决的技术问题是为克服现有技术中存在的缺少针对STING信号通路的小分子药物的缺陷，提供一种双链寡核苷酸DNA及其应用。
本发明人选择将重点放在STING上游，cGAS[环状GMP-AMP(cGAMP)]合酶，其为人们长期以来大力研究的STING依赖型胞质DNA传感器，可通过2'3'-cGAMP的合成激活STING信号通路。作为先天性和获得性免疫之间的重要桥梁，抗原呈递细胞[例如树突细胞(DC)]表达cGAS作为这些细胞中的DNA传感器。通过这些机制，免疫系统可以对各种DNA病毒和细菌感染产生有效的应答。
本发明提供一种双链寡核苷酸DNA，所述的双链寡核苷酸DNA的正义链的核苷酸序列包含如序列表中SEQ ID NO.19所示的核苷酸序列，反义链的核苷酸序列包含如序列表中SEQ ID NO.20所示的核苷酸序列；所述的正义链和所述的反义链的长度均为30bp以上；
或者，正义链的核苷酸序列如序列表中SEQ ID NO.3所示，反义链的核苷酸序列如序列表中SEQ ID NO.4所示；
或者，正义链的核苷酸序列如序列表中SEQ ID NO.17所示，反义链的核苷酸序列如序列表中SEQ ID NO.18所示。
较佳地，所述正义链的核苷酸序列如序列表中SEQ ID NO.11所示，所述的反义链的核苷酸序列如序列表中SEQ ID NO.12所示；
或者，所述正义链的核苷酸序列如序列表中SEQ ID NO.13所示，所述的反义链的核苷酸序列如序列表中SEQ ID NO.14所示；
或者，所述正义链的核苷酸序列如序列表中SEQ ID NO.15所示，所述的反义链的核苷酸序列如序列表中SEQ ID NO.16所示。
本发明还提供一种序列长度为30bp以上的双链寡核苷酸DNA在制备治疗STING信号通路相关的疾病的药物中的应用。
较佳地，所述的双链寡核苷酸DNA为如上所述的双链寡核苷酸DNA。
所述的STING信号通路相关的疾病为病毒感染或者肿瘤；所述的病毒可为本领域常规的病毒，例如流感病毒、疱疹病毒等。
本发明还提供一种STING信号通路激活剂，其包含如上所述的双链寡核苷酸DNA。
较佳地，所述的STING信号通路激活剂为治疗病毒感染或者肿瘤的药物。
本发明还提供一种药盒，其包括药盒A和药盒B，所述的药盒A包含如上所述的双链寡核苷酸DNA，所述的药盒B包含抗肿瘤药物。
其中，所述的抗肿瘤药物优选免疫药物。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明找到最短的DNA片段，使得将来产业化时合成容易，降低成本。同时短DNA也可能使得体内系统给药的配方相对容易开发。最后，小片段DNA相对体内细胞内毒性可能将较低。本发明人测试了不同长度的dsDNA，意外发现40个核苷酸是充分激活cGAS并激发IFN-β的最小dsDNA长度。
附图说明
图1为2种不同长度的dsDNA在细胞内的激活效应。
图2为6种不同长度的dsDNA在细胞内的激活效应。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
以下实施例中所用的THP-1细胞市售可得；所用的RNA提取试剂盒为RNApureTissure&Cell Kit；所用的反转录试剂盒为HiFiScript cDNA Synthesis Kit；所用的荧光定量PCR试剂为UltraSYBR Mixture。
实施例1
合成2对不同长度的随机序列的oligo DNA，(序列如表1)，通过PCR仪退火形成2条对应长度的dsDNA。
将适量生长状态良好的THP-1细胞接种至24孔细胞培养板中，在37℃，5％CO2培养箱中孵育过夜。随后将2-3μg不同长度的dsDNA分别转染细胞(转染的方法为本领域常规操作)，转染后细胞继续在37℃，5％CO2培养箱中孵育8-9小时。
孵育完成后，收集细胞，提取细胞总RNA。以RNA为模板，用RT-PCR方法检测IFN-β基因(引物序列见表2)的表达量，GAPDH基因为内参。
表1不同长度的oligo DNA序列设计表
表2人IFN-β基因的上下游引物
| 引物 | 序列 | 碱基数目 |
| 上游引物 | AGGACAGGATGAACTTTGAC(SEQ ID NO.5) | 20 |
| 下游引物 | TGATAGACATTAGCCAGGAG(SEQ ID NO.6) | 20 |
结果显示，40bp的dsDNA序列能够有效激活STING信号通路(见图1)，可能是dsDNA序列的最佳长度。
实施例2
重新合成了6种不同长度的随机的oligo DNA序列(见表3)，按照实施例1的方法再次进行实验分析。
结果显示，dsDNA序列长度≥30bp时均能激活STING信号通路；而40bp的dsDNA序列的激活效应最强(图2)。因此，双链寡核苷酸DNA(dsDNA)序列在表达cGAS的细胞内能够有效激活STING信号通路，刺激细胞过量表达IFN-β，且40bp的dsDNA序列是最大程度激活STING信号通路的最短DNA片段长度。
表3不同长度的oligo DNA序列设计表
其中，5～7号正义链的共有序列为TGTCCCAATTCTTGTTGAATTAGAT(SEQ ID NO.19)；5～7号反义链的共有序列为ATCTAATTCAACAAGAATTGGGACA(SEQ ID NO.20)。
SEQUENCE LISTING
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<220>
<223> 正义链
<400> 7
cttgttgaat tagatggtga 20
<210> 8
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 8
tcaccatcta attcaacaag 20
<210> 9
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> 正义链
<400> 9
caattcttgt tgaattagat ggtga 25
<210> 10
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 10
tcaccatcta attcaacaag aattg 25
<210> 11
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> 正义链
<400> 11
tgtcccaatt cttgttgaat tagatggtga 30
<210> 12
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 12
tcaccatcta attcaacaag aattgggaca 30
<210> 13
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 正义链
<400> 13
tcactggagt tgtcccaatt cttgttgaat tagat 35
<210> 14
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 14
atctaattca acaagaattg ggacaactcc agtga 35
<210> 15
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> 正义链
<400> 15
tcactggagt tgtcccaatt cttgttgaat tagatggtga 40
<210> 16
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 16
tcaccatcta attcaacaag aattgggaca actccagtga 40
<210> 17
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> 正义链
<400> 17
tcactggagt tgtccattgt taatttagac gagtctgaag ctctccaatt cttgttgaat 60
<210> 18
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 18
attcaacaag aattggagag cttcagactc gtctaaatta acaatggaca actccagtga 60
<210> 19
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> 正义链
<400> 19
tgtcccaatt cttgttgaat tagat 25
<210> 20
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> 反义链
<400> 20
atctaattca acaagaattg ggaca 25
Claims (10)
1.一种双链寡核苷酸DNA，其特征在于，其中正义链的核苷酸序列包含如序列表中SEQID NO.19所示的核苷酸序列，反义链的核苷酸序列包含如序列表中SEQ ID NO.20所示的核苷酸序列；所述的正义链和所述的反义链的长度均为30bp以上；
或者，正义链的核苷酸序列如序列表中SEQ ID NO.3所示，反义链的核苷酸序列如序列表中SEQ ID NO.4所示；
或者，正义链的核苷酸序列如序列表中SEQ ID NO.17所示，反义链的核苷酸序列如序列表中SEQ ID NO.18所示。
2.如权利要求1所述的双链寡核苷酸DNA，其特征在于，所述正义链的核苷酸序列如序列表中SEQ ID NO.11所示，所述的反义链的核苷酸序列如序列表中SEQ ID NO.12所示；
或者，所述正义链的核苷酸序列如序列表中SEQ ID NO.13所示，所述的反义链的核苷酸序列如序列表中SEQ ID NO.14所示；
或者，所述正义链的核苷酸序列如序列表中SEQ ID NO.15所示，所述的反义链的核苷酸序列如序列表中SEQ ID NO.16所示。
3.序列长度为30bp以上的双链寡核苷酸DNA在制备治疗STING信号通路相关的疾病的药物中的应用。
4.如权利要3所述的应用，其特征在于，所述的双链寡核苷酸DNA为权利要求1或2所述的双链寡核苷酸DNA。
5.如权利要求3或4所述的应用，其特征在于，所述的疾病为病毒感染或者肿瘤。
6.如权利要求5所述的应用，其特征在于，所述的病毒感染中的病毒为流感病毒或者疱疹病毒。
7.一种STING信号通路激活剂，其特征在于，其包含如权利要求1或2所述的双链寡核苷酸DNA。
8.如权利要求7所述的STING信号通路激活剂，其特征在于，所述的STING信号通路激活剂为治疗病毒感染或者肿瘤的药物。
9.一种药盒，其包括药盒A和药盒B，其特征在于，所述的药盒A包含如权利要求1或2所述的双链寡核苷酸DNA，所述的药盒B包含抗肿瘤药物。
10.如权利要求9所述的药盒，其特征在于，所述的抗肿瘤药物为免疫药物。
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