CN116790636A - 一种编码表达新城疫病毒抗原的信使核酸分子 - Google Patents
一种编码表达新城疫病毒抗原的信使核酸分子 Download PDFInfo
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Abstract
本发明涉及的是医药技术领域的一种肝脏靶向性多肽、组合物及其应用,其中所述肝脏靶向性组合物为氨基酸序列通式为TYKSGIGIDSGPKSGK的多肽与N‑乙酰基神经氨酸形成的组合物。此组合物可结合核酸形成大小均一的复合物颗粒,从而实现核酸药物的肝脏靶向性递送。
Description
技术领域
本发明涉及兽用生物制品技术领域,具体的,涉及基于mRNA的表达新城疫病毒蛋白抗原序列片段、变体或衍生物,可用于预防和治疗新城疫病毒感染导致的疾病的用途。
背景技术
新城疫病毒(Newcastle disease virus,NDV)属于副黏腺病毒科禽腮腺炎病毒属,是一种单链RNA病毒,其基因组突变频率较高。每次大规模流行都是由新基因型的毒株所引发。新城疫症状表现为突然死亡,或精神萎靡,不产蛋或产软壳蛋、畸形蛋,产量下降。鸡表现为咳嗽症状,下痢排黄绿色稀粪等。给禽类养殖业造成严重的经济损失。
目前国内在一般采用灭活疫苗、弱毒疫苗、亚单位疫苗等。但随着新城疫病毒的变异,传统疫苗免疫效果相对较差、不能很快应对新毒株以及生成成本高的问题亟需新的疫苗方式来替代。mRNA疫苗是最新的疫苗技术,本发明可以满足上述这些需求。
发明内容
本发明提供一种预防和治疗新城疫病毒引起疾病的人工设计的核糖核酸分子。该核酸分子可以用于制备预防新城疫病毒导致的疾病的疫苗,也可以应用于治疗相应疾病。新城疫病毒可以指Class I或Class II两大类各种不同的基因型。
本发明提供了一种编码表达新城疫病毒抗原的信使核酸分子,所述核酸分子的编码蛋白序列选自新城疫病毒编码蛋白的全长或部分序列;所述核酸分子的编码蛋白序列与SEQ ID NO:1有75%、80%、85%、90%、95%或99%相同的氨基酸序列,或所述核酸分子的编码蛋白序列与SEQ ID NO:1功能相同的序列。
进一步的,所述核酸分子包含SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6中的多条序列,所述核酸分子与SEQ ID NO:2、SEQ ID NO:3、SEQ IDNO:4、SEQ ID NO:5和SEQ ID NO:6中的至少一条序列有70%-100%的同源性,所述核酸分子的开放阅读框编码病毒蛋白全长或部分肽段序列。
进一步的,核酸分子的编码包含异源的肽段,异源的肽段与核酸分子形成融合蛋白。
进一步的,异源肽段可以为信号肽、其到辅助蛋白形成多聚结构的肽段。
进一步的,核酸分子序列中的核苷包含1种或多种化学修饰核苷,所述化学修饰核苷包括5-甲基胞苷、假尿苷、N-1-甲基-假尿苷和N-6-甲基腺苷。
进一步的,核苷修饰比例为1%-70%。
进一步的,核苷修饰比例为5%-70%。
进一步的,核苷修饰比例为10%-60%。
进一步的,核苷修饰比例为20%-60%。
进一步的,核苷修饰比例为30%-60%。
进一步的,核苷修饰比例为40%-50%。
进一步的,核苷修饰比例为50%。
在一些实施方案中,人工设计的核酸分子编码衍生自新城疫病蛋白或肽段序列。在一些实施方案中,所述蛋白为NH蛋白。
在一些实施方案中,所述的mRNA序列由SEQ ID NO:3-6组成。
在一些实施方案中,所述的mRNA序列含有帽子结构,具体的为Cap1。
在一些实施方案中,所述的mRNA序列含有经过修饰的核苷1-甲基假尿嘧啶,其与尿苷的比例为50%:50%。
本发明至少具备以下一种或多种有益效果:
本发明的核酸分子针对突变频率高的新城疫病毒具有免疫效果好、能很快对应新毒株、生产成本低等优点;
核酸分子可以用于制备预防新城疫病毒导致的疾病的疫苗,也可以用于治疗相应疾病。新城疫病毒指Class I或Class II两大类各种不同的基因型的新城疫病毒。
附图说明
下述附图进一步举例说明本发明,它们不应该由此解释为限制本发明的主题。
图1为核酸分子设计示意图,显示载体的结构与合成的mRNA组合体;
图2为制备的核酸琼脂糖电泳图。
具体实施方式
为了使本发明的内容以及其优点更为清晰易懂,下面结合附图1-2来对具体实施方案进行进一步完整地描述。具体实施方案仅作为本发明的示范性列举,不构成对本发明的范围有任何限制。基于本发明中的实施例的原理,本领域技术人员通过对本发明技术方案进行局部细节的修改、等同或替代所得的其他实施例均属于本发明的保护范围。
除非另外指出,否则本发明中的实施方案可采用通常的有机化学、材料学、分子生物学、细胞生物学、免疫学、兽医学的常规技术和定义。这些常规技术的方案可来自于制造商的产品说明书或标准实验手册中,或相类似的参考文献。
实施例1:体外转录模板的制备
模板质粒的全基因合成:一个完整的编码NDV NH蛋白SEQ ID NO:1的mRNA表达功能区块需要将含有T7启动子序列SEQ ID NO:2、5‘UTR区SEQ ID NO:3、ORF区SEQ ID NO:4、3‘UTR区SEQ ID NO:5以及polyA SEQ ID NO:6的DNA序列串联排布。上述序列组合克隆于pUC57载体多克隆位点EcoRI/HindIII酶切位点之间。
线性化体外转录模板制备:将质粒进行酶切线性化,再利用PCR反应可以得到大量扩增产物,反应中使用引物:正向SEQ ID NO:7;反向SEQ ID NO:8
配置反应体系包含:5X Phusion Buffer 50μL;dNTP 2μL;正向引物1μL;反向引物1μL;模板质粒0.5μL;Phusion Enzyme 2μL;H2O 194.5μL;
反应条件:98℃30s循环28次;72℃10min;4℃恒温;当然,还可以采用以下参数循环28次,如98℃10s;55℃20s;72℃10s或72℃120s;、等参数。
离心柱法纯化PCR产物;
实施例2:mRNA的制备
体外转录体系:利用T7RNA聚合酶大量产生与模板DNA可转录部分序列相同的核糖核酸序列。按照如下配比混合:10X Buffer 2μL、ATP(100mM)2μL、CTP(100mM)2μL、GTP(100mM)2μL、UTP(100mM)1μL、m1ψTP(100mM)1μL、线性DNA模板1μL和T7 enzyme 2μL;然后用H2O将体系总体积补至20μL;体系混匀后在37度反应3小时,然后添加1U/μL DNase I 1μL消化DNA模板,混匀后处理30min。产物RNA通过加入1/10体积的8M LiCl,在-20℃沉淀1h,通过4℃15000g 20min离心,去上清并用75%乙醇漂洗两次沉淀。RNA干燥后用无核酶的水溶解。
加Cap1帽子:前述制得的RNA需要进行加热至60℃5min,然后急速置于冰上放5min。配置加帽体系:RNA 10μg、10X capping Buffer 2μL、GTP(10mM)1μL、SAM(2mM)1μL、Vaccina Capping Enzyme 1μL和2’-O-methyltransferase1μL;然后用H2O将加帽体系总体积补至20μL;反应体系在37℃下保持30分钟。加帽的mRNA通过加入1/10体积的8M LiCl,在-20℃沉淀1h,通过4℃15000g20min离心,去上清并用75%乙醇漂洗两次沉淀。RNA干燥后用无核酶的水溶解,置于-80℃长期保存。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改和变型。
序列表
<110> 苏州慧疗生物医药科技有限公司
<120> 一种编码表达新城疫病毒抗原的信使核酸分子
<130> JL202214407HL
<141> 2022-03-17
<160> 8
<170> SIPOSequenceListing 1.0
<210> 1
<211> 577
<212> PRT
<213> 人工序列
<400> 1
Met Asp Arg Ala Val Ser Gln Val Ala Leu Glu Asn Asp Glu Arg Glu
1 5 10 15
Ala Lys Asn Thr Trp Arg Leu Ile Phe Arg Ile Ala Ile Leu Phe Leu
20 25 30
Thr Val Val Thr Leu Ala Ile Ser Val Ala Ser Leu Leu Tyr Ser Met
35 40 45
Gly Ala Ser Thr Pro Ser Asp Leu Val Gly Ile Pro Thr Arg Ile Ser
50 55 60
Arg Ala Glu Glu Lys Ile Thr Ser Thr Leu Gly Ser Asn Gln Asp Val
65 70 75 80
Val Asp Arg Ile Tyr Lys Gln Val Ala Leu Glu Ser Pro Leu Ala Leu
85 90 95
Leu Asn Thr Glu Thr Thr Ile Met Asn Ala Ile Thr Ser Leu Ser Tyr
100 105 110
Gln Ile Asn Gly Ala Ala Asn Asn Ser Gly Trp Arg Ala Pro Ile His
115 120 125
Asp Pro Asp Tyr Ile Gly Gly Ile Gly Lys Glu Leu Ile Val Asp Asp
130 135 140
Ala Ser Asp Val Thr Ser Phe Tyr Pro Ser Ala Phe Gln Glu His Leu
145 150 155 160
Asn Phe Ile Pro Ala Pro Thr Thr Gly Ser Gly Cys Thr Arg Ile Pro
165 170 175
Ser Phe Asp Met Ser Ala Thr His Tyr Cys Tyr Thr His Asn Val Ile
180 185 190
Leu Ser Gly Cys Arg Asp His Ser His Ser Tyr Gln Tyr Leu Ala Leu
195 200 205
Gly Val Leu Arg Thr Ser Ala Thr Gly Arg Val Phe Phe Ser Thr Leu
210 215 220
Arg Ser Ile Asn Leu Asp Asp Thr Gln Asn Arg Lys Ser Cys Ser Val
225 230 235 240
Ser Ala Thr Pro Leu Gly Cys Asp Met Leu Cys Ser Lys Val Thr Glu
245 250 255
Thr Glu Glu Glu Asp Tyr Asn Ser Ala Val Pro Thr Arg Met Val His
260 265 270
Gly Arg Leu Gly Phe Asp Gly Gln Tyr His Glu Lys Asp Leu Asp Val
275 280 285
Thr Thr Leu Phe Gly Asp Trp Val Ala Asn Tyr Pro Gly Val Gly Gly
290 295 300
Gly Ser Phe Ile Asp Ser Arg Val Trp Phe Ser Val Tyr Gly Gly Leu
305 310 315 320
Lys Pro Asn Ser Pro Ser Asp Thr Val Gln Glu Gly Lys Tyr Val Ile
325 330 335
Tyr Lys Arg Tyr Asn Asp Thr Cys Pro Asp Glu Gln Asp Tyr Gln Ile
340 345 350
Arg Met Ala Lys Ser Ser Tyr Lys Pro Gly Arg Phe Gly Gly Lys Arg
355 360 365
Ile Gln Gln Ala Ile Leu Ser Ile Lys Val Ser Thr Ser Leu Gly Glu
370 375 380
Asp Pro Val Leu Thr Val Pro Pro Asn Thr Val Thr Leu Met Gly Ala
385 390 395 400
Glu Gly Arg Ile Leu Thr Val Gly Thr Ser His Phe Leu Tyr Gln Arg
405 410 415
Gly Ser Ser Tyr Phe Ser Pro Ala Leu Leu Tyr Pro Met Thr Val Ser
420 425 430
Asn Lys Thr Ala Thr Leu His Ser Pro Tyr Thr Phe Asn Ala Phe Thr
435 440 445
Arg Pro Gly Ser Ile Pro Cys Gln Ala Ser Ala Arg Cys Pro Asn Ser
450 455 460
Cys Val Thr Gly Val Tyr Thr Asp Pro Tyr Pro Leu Ile Phe Tyr Arg
465 470 475 480
Asn His Thr Leu Arg Gly Val Phe Gly Thr Met Leu Asp Gly Val Gln
485 490 495
Ala Arg Leu Asn Pro Ala Ser Ala Val Phe Asp Gly Thr Ser Arg Ser
500 505 510
Arg Ile Thr Arg Val Ser Ser Ser Ser Thr Lys Ala Ala Tyr Thr Thr
515 520 525
Ser Thr Cys Phe Lys Val Val Lys Thr Asn Lys Thr Tyr Cys Leu Ser
530 535 540
Ile Ala Glu Ile Ser Asn Thr Leu Phe Gly Glu Phe Arg Ile Val Pro
545 550 555 560
Leu Leu Val Glu Ile Leu Lys Asp Asp Gly Val Arg Glu Ala Arg Ser
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Gly
<210> 2
<211> 20
<212> DNA
<213> 人工序列
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taatacgact cactataagg 20
<210> 3
<211> 100
<212> DNA
<213> 人工序列
<400> 3
gggagtcgct gcgcgctgcc ttcgccccgt gccccgctcc gccgccgcct cgcgccgccc 60
gccccggctc tgactgaccg cgttactccc acagccagcc 100
<210> 4
<211> 1731
<212> DNA
<213> 人工序列
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atggaccggg ccgtgagcca ggtggccctg gagaacgacg agcgggaggc caagaacacc 60
tggcggctga tcttccggat cgccatcctg ttcctgaccg tggtgaccct ggccatcagc 120
gtggccagcc tgctgtacag catgggcgcc agcaccccca gcgacctggt gggcatcccc 180
acccggatca gccgggccga ggagaagatc accagcaccc tgggcagcaa ccaggacgtg 240
gtggaccgga tctacaagca ggtggccctg gagagccccc tggccctgct gaacaccgag 300
accaccatca tgaacgccat caccagcctg agctaccaga tcaacggcgc cgccaacaac 360
agcggctggc gggcccccat ccacgacccc gactacatcg gcggcatcgg caaggagctg 420
atcgtggacg acgccagcga cgtgaccagc ttctacccca gcgccttcca ggagcacctg 480
aacttcatcc ccgcccccac caccggcagc ggctgcaccc ggatccccag cttcgacatg 540
agcgccaccc actactgcta cacccacaac gtgatcctga gcggctgccg ggaccacagc 600
cacagctacc agtacctggc cctgggcgtg ctgcggacca gcgccaccgg ccgggtgttc 660
ttcagcaccc tgcggagcat caacctggac gacacccaga accggaagag ctgcagcgtg 720
agcgccaccc ccctgggctg cgacatgctg tgcagcaagg tgaccgagac cgaggaggag 780
gactacaaca gcgccgtgcc cacccggatg gtgcacggcc ggctgggctt cgacggccag 840
taccacgaga aggacctgga cgtgaccacc ctgttcggcg actgggtggc caactacccc 900
ggcgtgggcg gcggcagctt catcgacagc cgggtgtggt tcagcgtgta cggcggcctg 960
aagcccaaca gccccagcga caccgtgcag gagggcaagt acgtgatcta caagcggtac 1020
aacgacacct gccccgacga gcaggactac cagatccgga tggccaagag cagctacaag 1080
cccggccggt tcggcggcaa gcggatccag caggccatcc tgagcatcaa ggtgagcacc 1140
agcctgggcg aggaccccgt gctgaccgtg ccccccaaca ccgtgaccct gatgggcgcc 1200
gagggccgga tcctgaccgt gggcaccagc cacttcctgt accagcgggg cagcagctac 1260
ttcagccccg ccctgctgta ccccatgacc gtgagcaaca agaccgccac cctgcacagc 1320
ccctacacct tcaacgcctt cacccggccc ggcagcatcc cctgccaggc cagcgcccgg 1380
tgccccaaca gctgcgtgac cggcgtgtac accgacccct accccctgat cttctaccgg 1440
aaccacaccc tgcggggcgt gttcggcacc atgctggacg gcgtgcaggc ccggctgaac 1500
cccgccagcg ccgtgttcga cggcaccagc cggagccgga tcacccgggt gagcagcagc 1560
agcaccaagg ccgcctacac caccagcacc tgcttcaagg tggtgaagac caacaagacc 1620
tactgcctga gcatcgccga gatcagcaac accctgttcg gcgagttccg gatcgtgccc 1680
ctgctggtgg agatcctgaa ggacgacggc gtgcgggagg cccggagcgg c 1731
<210> 5
<211> 196
<212> DNA
<213> 人工序列
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taatgataac gcccgttgcg aacctaacgc tgtttaaaca ccaaggctct tttcagagcc 60
acccacacat tcacaacgag agctgtttat tacttgagca tcgttaataa aaaaacaagg 120
ttttgctact ttttgtaaag tacaattttt cttatatatg cggggggaaa agaaagcaat 180
tacagccctt tgtaag 196
<210> 6
<211> 120
<212> DNA
<213> 人工序列
<400> 6
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 60
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 120
<210> 7
<211> 31
<212> DNA
<213> 人工序列
<400> 7
gggttttccc agtcacgacg ttgtaaaacg a 31
<210> 8
<211> 142
<212> DNA
<213> 人工序列
<400> 8
tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt 60
tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt 120
cttacaaagg gctgtaattg ct 142
Claims (12)
1.一种编码表达新城疫病毒抗原的信使核酸分子,其特征在于,所述核酸分子的编码蛋白序列选自新城疫病毒编码蛋白的全长或部分序列;
所述核酸分子的编码蛋白序列与SEQ ID NO:1有75%、80%、85%、90%、95%或99%相同的氨基酸序列,或
所述核酸分子的编码蛋白序列与SEQ ID NO:1功能相同的序列。
2.根据权利要求1的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,所述核酸分子包括SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6中的多条序列,所述核酸分子与SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5和SEQ IDNO:6中的至少一条序列有70%-100%的同源性,所述核酸分子的开放阅读框编码病毒蛋白全长或部分肽段序列。
3.根据权利要求2所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核酸分子的编码包含异源的肽段,异源的肽段与核酸分子形成融合蛋白。
4.根据权利要求3所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,异源肽段可以为信号肽、其到辅助蛋白形成多聚结构的肽段。
5.根据权利要求1-4任一项所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核酸分子序列中的核苷包含1种或多种化学修饰核苷,所述化学修饰核苷包括5-甲基胞苷、假尿苷、N-1-甲基-假尿苷和N-6-甲基腺苷。
6.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为1%-70%。
7.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为5%-70%。
8.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为10%-60%。
9.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为20%-60%。
10.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为30%-60%。
11.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为40%-50%。
12.根据权利要求5所述的编码表达新城疫病毒抗原的信使核酸分子,其特征在于,核苷修饰比例为50%。
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