CN115003690B - 重组生长分化因子11(gdf11) - Google Patents
重组生长分化因子11(gdf11) Download PDFInfo
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- CN115003690B CN115003690B CN202180007896.4A CN202180007896A CN115003690B CN 115003690 B CN115003690 B CN 115003690B CN 202180007896 A CN202180007896 A CN 202180007896A CN 115003690 B CN115003690 B CN 115003690B
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Abstract
本发明的目的是产生具有免疫活性的重组GDF11蛋白,该重组GDF11蛋白易于纯化并相对于生长分化因子11蛋白具有足够的免疫原性,可用于通过诱导合成GDF11的特异性自身抗体、阻断GDF11的作用,从而刺激肌肉组织生长来增加哺乳动物和鸟类的肌肉量。本发明通过产生包含GDF11和葡聚糖结合结构域的重组蛋白来实现。本发明提出了用于生产在葡聚糖上的靶蛋白的方法,该方法涉及使蛋白与含葡聚糖的吸附剂通过亲和作用结合,随后洗去未结合的细菌蛋白并回收目标产物。
Description
技术领域
本组发明涉及基因工程、生物技术和兽医学,具体涉及重组生长分化因子11、其生产方法、含有作为抗原的GDF11的免疫原性组合物、用于增加哺乳动物和家禽肌肉量的注射剂,以及使用指定注射剂增加动物肌肉量的方法。
背景技术
生长分化因子11(GDF11)蛋白属于转化生长因子-β的TGF-β超家族。GDF11是一种肌肉生长抑制素同源蛋白,可作为各种组织的生长抑制剂。GDF11能够与肌肉生长抑制素结合相同的TGF-βI型超家族ACVR1B(ALK4)、TGFBR1(ALK5)和ACVR1C(ALK7)的受体,但主要使用ALK4和ALK5来进行信号传递(AnderssonО,ReissmannЕ,Ibanez CF,2006年,EMBOReports.,第7卷第8期:第831-837页)。
在现有技术中已知美国专利号6096506,其公开了与肌肉生长抑制素多肽特异性反应的抗体。还已知以下方法:通过引入对抗肌肉生长抑制素并阻断其活性的单克隆抗体来增加动物肌肉量的方法(美国专利号6468535),以及生产具有肌肉生长抑制素序列并且能够诱导合成肌肉生长抑制素的特异性自身抗体作为免疫原性组合物的一部分、阻断该肌肉生长抑制素作用,从而刺激肌肉组织生长的融合蛋白的方法(俄罗斯联邦专利号2613420)。
GDF11与肌肉生长抑制素(一种负性肌肉生长调节剂)密切相关。(McPherron AC,Lee SJ,1997年,Proc.Natl.Acad.Sci.U.S.A.,第94卷第23期:第12457-12461页)。肌肉生长抑制素和GDF11参与心肌细胞增殖调节。GDF11和肌肉生长抑制素之间的相似性意味着可能使用了参与调节组织大小(肌肉和骨骼以及软骨大小)的相同调节机制。(EgermanМА等人,Cell Metab.,2015年第22卷第l期:第164-174页;Zimmers TA等人,2017年,Basic ResCardiol.,第112卷第4期:第48页)。因此,阻断GDF11活性应导致身体肌肉量的显著增加。
本发明的作者获得了意想不到的可重复结果,证明了含有GDF11的融合重组蛋白、含有该蛋白的免疫原性组合物以及疫苗可用于增加身体的肌肉量。
发明内容
待由所要求保护的一组发明组解决的技术问题涉及产生具有免疫活性的重组GDF11,该重组GDF11易于纯化并且相对于作为抗原的GDF11具有足够的免疫原性,可用于通过诱导合成GDF11的特异性自身抗体、阻断GDF11的作用,从而刺激肌肉组织生长来提高家畜(牛、猪、马、兔等)和家禽的产肉率。待由所要求保护的一组发明解决的另一个技术问题涉及开发基于指定蛋白质的药物和建立使用该药物的方法,该方法解决了在非系统地使用该药物的情况下提高家畜和家禽的产肉率的问题。应当注意,GDF11的氨基酸序列在所有哺乳动物和鸟类中都是相同的。因此,所开发的产品是提高家畜和家禽的产肉率的通用药剂。
通过实施所要求保护的一组发明而实现的技术成果涉及能够提高家畜和家禽生产力的工具和方法集的扩展。
该技术成果通过分子量为35.9kDa的重组蛋白来实现,该重组蛋白包括:具有SEQID NO:1的序列的生长分化因子11(GDF11)蛋白的片段、具有SEQ ID NO:2的序列的Gly-Ser间隔区、具有SEQ ID NO:3的序列的来自变异链球菌(Streptococcus mutans)的基因的α葡聚糖结合结构域(GBD)和具有SEQ ID NO:4的GDF11-GBD基因核苷酸序列。
该技术成果还通过生产含葡聚糖的GDF11(GDF11-GBD)重组蛋白的方法来实现,该方法包括:
—培养表达GDF11-GBD基因的大肠杆菌(E.coli)细胞;
—使大肠杆菌菌株BL21[pGDF11-GBD]的细胞提取物中的GDF11-GBD蛋白与含葡聚糖(含α-葡聚糖)的吸附剂在孵育过程中通过亲和作用结合;
—随后进行洗涤以除去未结合的细菌蛋白并回收目标产物。
普鲁兰多糖、糖原、右旋糖酐和淀粉可用作含葡聚糖的吸附剂(葡聚糖、α葡聚糖)。
GDF11-GBD重组蛋白包括葡聚糖结合结构域的决定该蛋白与含葡聚糖的吸附剂结合的能力的蛋白序列,这使得浓缩、纯化以及将蛋白产物固定在葡聚糖(α葡聚糖,含葡聚糖吸附剂)上仅需一个步骤。来自变异链球菌的基因的α葡聚糖结合结构域中的葡聚糖结合结构域的存在确保了在葡聚糖上固定,该变异链球菌基因的α葡聚糖结合结构域对α葡聚糖具有高亲和力,并且在重组蛋白中pH值为6.0至9.0和盐浓度为0M至3M NaCl的大范围内提供与该含葡聚糖吸附剂的不可逆结合。
由于大肠杆菌细胞中不存在α葡聚糖结合蛋白,因此在大肠杆菌细胞中合成的GDF11-GBD重组蛋白是生产菌株细胞中与α葡聚糖强烈结合的唯一蛋白。这使得固定在含葡聚糖吸附剂上的高度纯化的重组蛋白制剂的单阶段生产成为可能。
技术成果还通过以下实现:用于增加家畜和家禽的肌肉量的注射剂,该注射剂含有如上所述的GDF11-GBD重组蛋白,该重组蛋白悬浮于可用于注射的含葡聚糖(α-葡聚糖)的吸附剂的液体佐剂(载体)溶液的环境中;以及实施用于增加家畜和家禽的肌肉量的方法,该方法包括将含有GDF11-GBD重组蛋白的药物以0.5-50μg指定蛋白/kg动物或家禽体重进行皮下或肌内注射,该重组蛋白悬浮于可用于注射的含葡聚糖(α-葡聚糖)的吸附剂的液体载体溶液的环境中。
因此,已经产生的双功能GDF11-GBD重组蛋白能够自发与含葡聚糖的吸附剂结合,形成多抗原形式的高度免疫原性组合物,以在施用给动物时诱导合成GDF11的特异性自身抗体,从而刺激肌肉组织生长。
GDF11(GDF11-GBD)重组融合蛋白的生产
在第一阶段获得GDF11基因,随后对该基因进行克隆。
使用化学发酵方法获得GDF11基因。已经设计了编码相应基因的寡核苷酸双链体,优化后可在大肠杆菌中表达。然后获得含有编码GDF11、间隔区和葡聚糖结合结构域(GBD)的序列的pGDF11-GBD质粒。
获得生产与葡聚糖结合结构域结合的GDF-11重组抗原的大肠杆菌菌株
用pGDF11-GBD质粒转化大肠杆菌BL21细胞,以获得生产GDF11-GBD重组蛋白的大肠杆菌菌株。向培养物中补充3μL的0.1M异丙基-β-D-硫代吡喃半乳糖苷(IPTG)溶液,并且在37℃的温度培养3小时。在比较由大肠杆菌菌株BL21细胞[pGDF11-GBD]合成的蛋白质的谱时,发现了另外的蛋白质条带。这条额外条带的分子量与GDF11-GBD重组蛋白预期的35.9kDa的质量一致。通过比较该重组蛋白的条带与标准分子量的对应蛋白的条带的染色强度,确定大肠杆菌中蛋白质合成的水平。已经表明,GDF11-GBD重组蛋白在大肠杆菌细胞中以包涵体形式的不溶形式合成。
α-葡聚糖固定化GDF11-GBD重组蛋白(GDF11)的生产
大肠杆菌菌株BL21[pGDF11-GBD]的细胞培养物在37℃在1,000mL含有氨苄青霉素(100μg/mL)的LB培养基中培养至波长为550nm时对应1单位吸收的光密度,以获得重组蛋白。向培养基中加入15μL的0.1MIPTG溶液,并且培养3小时。通过以5,500g离心15分钟来沉淀细胞。
将沉淀物重悬于含有溶菌酶的磷酸盐缓冲液中。再将悬浮液超声处理。在以6,000g离心后,不溶的GDF11-GBD蛋白留在沉淀物中。将沉淀物悬浮于8M尿素中,以12,000g离心30分钟,除去上清液。为了将GDF11-GBD重组蛋白固定在含葡聚糖的吸附剂上,将上清液用中性pH的生理磷酸盐缓冲液稀释四倍,加入1/10体积的α葡聚糖悬浮液(普鲁兰多糖、糖原或右旋糖酐或淀粉),并将该上清液以25℃孵育2小时。以8,000rpm的速度离心,将沉淀物重悬于磷酸盐缓冲液中;用α葡聚糖重复洗涤3次。固定在α葡聚糖上的GDF11-GBD抗原代表其上吸附有蛋白的吸附剂的悬浮液。制剂的纯度为至少90%。通过加入苯甲醇至浓度为0.1%来保存该制剂。
GDF11-GBD重组蛋白的生物学作用
在本发明的优选实施方案中,制剂含有GDF-11-GBD重组蛋白的中性pH缓冲溶液,该重组蛋白悬浮于以下佐剂中:葡聚糖溶液与水油悬浮液MONTANIDE ISA 206VG(50重量%/50重量%)或MONTANIDE ISA 70VG(30重量%/70重量%)的混合物,或与2%、3%或6%氢氧化铝悬浮液(5体积%/30体积%)的混合物;或按照制造商的使用说明的其他商业佐剂与葡聚糖溶液的混合物,并且该制剂以0.5-150μg重组蛋白/1kg动物或家禽体重的剂量用作皮下或肌内注射药物一次或两次,注射间隔为20-30天。该药物的作用机制是基于在自身抗体的帮助下暂时阻断内源性GDF11的活性。
通过以下实施例来说明该药物在增加家畜的瘦体重方面的功效。
实施例1.含有GDF11-GBD重组蛋白的药物对仔猪体重增加的影响
在工业化的养猪场中,以0.10-150μg重组蛋白/1kg动物体重的比率分两次向90-120天大、体重为20-25kg的Large White仔猪注射含有悬浮于佐剂介质(α葡聚糖(50重量%)和水油悬浮液MONTANIDE ISA206VG(50重量%)的混合物)中的GDF11-GBD重组蛋白的药物,两次注射间隔21天。药物采用皮下注射方式。实验组和对照组各10只动物。对照组的动物不接受任何注射。结果示于表1中。
表1
所示的数据表明,两次(间隔21天)注射含有GDF11-GBD重组蛋白的药物使得仔猪的体重在以0.5μg/kg的重组蛋白的剂量第二次注射药物90天后,相对于对照组中的该指标增加13.4%;当施用重组蛋白剂量为50μg/kg的药物时,这一结果为28.8%;当施用重组蛋白剂量为100μg/kg的药物时,这一结果为28.6%。因此,当以0.5μg/kg至150μg/kg范围的剂量施用药物时,仔猪的体重增加相对于对照组中的增加有显著增加。
此外,还发现即使单次施用含有GDF11-GBD重组蛋白的药物也能使仔猪的体重显著增加。
值得注意的是,当以超出0.5-150μg/kg的剂量范围的剂量施用药物时,仔猪的体重增加相对于对照组中的体重增加有显著下降。
表2示出了用含有GDF11-GBD重组蛋白的药物免疫后,仔猪血清中相对于肌肉生长抑制素的自身抗体水平(ELISA法)。
表2
用含有GDF11-GBD重组蛋白的药物进行免疫的仔猪血清样品中GDF11的自身抗体水平的ELISA测定结果
表1和表2表明,含有GDF11-GBD重组蛋白的药物在动物体内诱导自身抗体的最佳剂量为0.5-150mg/kg动物体重。
实施例2.含有GDF11-GBD重组蛋白的药物对Kholmogory公牛体重增加的影响
在养殖场中,以0.1-150μg重组蛋白/1kg动物活体重的比率分两次向3个月大的Kholmogory小牛注射含有悬浮于佐剂介质(α葡聚糖(50重量%)和水油悬浮液MONTANIDEISA 206VG(50重量%)的混合物)中的GDF11-GBD重组蛋白的药物,两次注射间隔25天。
将药物皮下注射到颈部下方的三分之一处。实验组和对照组各10只动物。对照组的动物不接受任何注射。
结果示于表3中。
表3
数据表明,两次(间隔25天)施用含有GDF11-GBD重组蛋白的药物使得小牛的体重在以0.5μg/kg的重组蛋白的剂量第二次注射药物90天后,相对于对照组中的该指标增加6.4%;当施用重组蛋白质剂量为5μg/kg的药物时,这一结果为14.1%;当施用重组蛋白剂量为50μg/kg的药物时,这一结果为10.8%,当重组蛋白剂量增加一倍至100μg/kg或150μg/kg时,其体重增加22.1%。
因此,当以0.5μg/kg至150μg/kg范围的剂量施用药物时,小牛的体重增加相对于对照组中的增加有显著增加。
此外,还发现即使单次施用含有GDF11-GBD重组蛋白的药物也能使小牛的体重显著增加。
值得注意的是,当以超出0.5-150μg/kg的剂量范围的剂量施用药物时,小牛的体重增加相对于对照组中的增加有显著下降。
实施例3.含有GDF11-GBD重组蛋白的药物对羔羊体重增加的影响
以0.1-150μg重组蛋白/1kg动物活体重的比率分两次向2-3个月大的Romanov羔羊注射含有悬浮于佐剂介质(α葡聚糖(50重量%)和3%氢氧化铝(15体积%)悬浮液的混合物)中的GDF11-GBD重组蛋白的药物,两次注射间隔30天。药物采用肌内注射方式。实验组和对照组各10只动物。对照组的动物不接受任何注射。结果示于表4中。
表4
数据表明,两次(间隔30天)向Romanov羔羊施用含有GDF11-GBD重组蛋白的药物使得这些动物的体重在以0.5μg/kg的重组蛋白的剂量第二次注射药物90天后,相比于对照组中的该指标增加11.4%;当施用重组蛋白剂量为5μg/kg的药物时,这一结果为16.6%;当施用重组蛋白剂量为50μg/kg的药物时,这一结果为22.9%;当施用重组蛋白剂量为100μg/kg的药物时,这一结果为23.2%;当施用重组蛋白剂量为150μg/kg的药物时,这一结果为23.4%。
此外,还发现即使单次施用含有GDF11-GBD重组蛋白的药物也能使羔羊的体重显著增加。
值得注意的是,当以超出0.5-150μg/kg的剂量范围的剂量施用药物时,羔羊的体重增加相对于对照组中的增加有显著下降。
实施例4.含有GDF11-GBD重组蛋白的药物对兔体重增加的影响
以0.1-150μg重组蛋白/1kg动物活体重的比率分两次向2-3个月大的White Giant兔注射含有悬浮于佐剂介质(α葡聚糖(50重量%)和3%氢氧化铝(10体积%)悬浮液的混合物)中的GDF11-GBD重组蛋白的药物,两次注射间隔28天。药物采用肌内注射方式。实验组和对照组各10只动物。对照组的动物不接受任何注射。结果示于表5中。
表5
此外,还发现即使单次施用含有GDF11-GBD重组蛋白的药物也能使兔的体重显著增加。
值得注意的是,当以超出0.5-150μg/kg的剂量范围的剂量施用药物时,兔的体重增加相对于对照组中的增加有显著下降。
实施例5.含有GDF11-GBD重组蛋白的药物对火鸡体重增加的影响
向50-60天大的Broad Breasted White(重杂交)火鸡(雄性)施用含有重组蛋白的药物。以0.1、0.3、0.5、5、50、100、110、130、150μg/kg重组蛋白/1kg火鸡体重的剂量分两次施用含有悬浮于佐剂介质(α葡聚糖(30重量%)和水油悬浮液MONTANIDE ISA 70VG(70重量%)的混合物)中的GDF11-GBD重组蛋白的药物,两次施用间隔21天。药物采用肌内注射方式。实验组和对照组各10只动物。对照组的家禽不接受任何注射。结果示于表6中。
表6
数据表明,两次(间隔21天)向火鸡施用含有悬浮于佐剂介质(α葡聚糖(30重量%)和水油悬浮液MONTANIDE ISA 70VG(70重量%)的混合物)中的GDF11-GBD重组蛋白的药物使得这些动物的体重在以0.5μg/kg的重组蛋白的剂量第二次注射药物90天后,相比于对照组中的该指标增加8.4%;当施用重组蛋白剂量为5μg/kg的药物时,这一结果为11.4%;当施用重组蛋白剂量为50μg/kg的药物时,这一结果为21.1%;当施用重组蛋白剂量为150μg/kg的药物时,这一结果为21.6%。
此外,还发现即使单次施用含有GDF11-GBD重组蛋白的药物也能使火鸡的体重显著增加。
值得注意的是,当以超出0.5-150μg/kg的剂量范围的剂量施用药物时,火鸡的体重增加相对于对照组中的体重增加有显著下降。
本发明的上述示例并非穷举性的。其他可能的实施方案对应于本专利权利要求的范围。
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序列表
<110> IN-VET科技生产公司(Limited Liability Company “Scientific andProduction Corporation IN-VET”)
<120> 重组生长分化因子11(GDF11)
<150> 2020105836
<151> 2020-02-07
<160> 5
<170> SIPOSequenceListing 1.0
<210> 1
<211> 107
<212> PRT
<213> Artifical Sequence
<400> 1
Gly Leu Asp Cys Asp Glu His Ser Thr Glu Ser Arg Cys Cys Arg Tyr
1 5 10 15
Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp Asp Trp Ile Ile Ala
20 25 30
Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly Gln Cys Glu Tyr Met
35 40 45
Phe Met Gln Lys Tyr Pro His Thr His Leu Val Gln Gln Ala Asn Pro
50 55 60
Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr Lys Met Ser Pro Ile
65 70 75 80
Asn Met Leu Tyr Phe Asn Asp Lys Gln Gln Ile Ile Tyr Gly Lys Ile
85 90 95
Pro Gly Met Val Val Asp Arg Cys Gly Cys Ser
100 105
<210> 2
<211> 15
<212> PRT
<213> Artifical Sequence
<400> 2
Gly Ser Pro Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ala
1 5 10 15
<210> 3
<211> 180
<212> PRT
<213> Streptococcus mutans
<400> 3
Glu Leu Asn Arg Lys Asn Tyr His Tyr Gln Gln Phe Ile Thr Ala Tyr
1 5 10 15
Glu Asn Leu Leu Arg Asp Lys Val Glu Asn Asp Ser Ala Glu Pro Gln
20 25 30
Thr Phe Thr Ala Asn Gly Arg Gln Leu Ser Gln Asp Ala Leu Gly Ile
35 40 45
Asn Gly Asp Gln Val Trp Thr Tyr Ala Lys Lys Gly Asn Asp Phe Arg
50 55 60
Thr Ile Gln Leu Leu Asn Leu Met Gly Ile Thr Ser Asp Trp Lys Asn
65 70 75 80
Glu Asp Gly Tyr Glu Asn Asn Lys Thr Pro Asp Glu Gln Thr Asn Leu
85 90 95
Leu Val Thr Tyr Pro Leu Thr Gly Val Ser Met Ala Glu Ala Asp Arg
100 105 110
Ile Ala Lys Gln Val Tyr Leu Thr Ser Pro Asp Asp Trp Leu Gln Ser
115 120 125
Ser Met Ile Ser Leu Ala Thr Gln Val Lys Thr Asn Glu Asn Gly Asp
130 135 140
Pro Val Leu Tyr Ile Gln Val Pro Arg Leu Thr Leu Trp Asp Met Ile
145 150 155 160
Tyr Ile Asn Glu Thr Ile Lys Pro Glu Thr Pro Lys Val Pro Glu Gln
165 170 175
Pro Gln His Pro
180
<210> 4
<211> 1080
<212> DNA
<213> Artifical Sequence
<400> 4
ctcgagaaat cataaaaaat ttatttgctt tgtgagcgga taacaattat aatagattca 60
attgtgagcg gataacaatt tcacacagaa ttcattaaag aggagaaatt aactatgaga 120
ggatcgcatc accatcacca tcacggatcc ccgggttctg gctccggctc tggttccggt 180
tctggcgcca gatccgaact gaaccgcaaa aactatcatt atcagcagtt tattaccgcg 240
tatgaaaacc tgctgcgcga caaagtggaa aacgatagcg cggaaccgca gacctttacc 300
gcgaacggcc gccagctgag ccaggatgct ctgggcatta acggcgatca ggtgtggacc 360
tacgctaaaa aaggcaacga ttttcgcacc attcagctgc tgaacctgat gggcattacc 420
agcgactgga aaaacgaaga tggctatgaa aacaacaaaa ctccagatga acagaccaac 480
ctgctggtga cctacccgct gaccggtgtt tctatggctg aagctgatcg cattgcgaaa 540
caggtgtatc tgaccagccc ggatgattgg ctgcagagca gcatgattag cctggcgacc 600
caggtgaaaa ccaacgaaaa cggcgatccg gtgctgtata ttcaggtgcc gcgcctgacc 660
ctgtgggata tgatttatat taacgaaacc attaaaccgg aaaccccgaa agtgccggaa 720
cagccgcagc atccgagatc cggctctggt tctggtctgg actgcgacga acactctacc 780
gaatctcgtt gctgccgtta cccgctgacc gttgacttcg aagcgttcgg ttgggactgg 840
atcatcgctc cgaaacgtta caaagctaac tactgctctg gacagtgcga atacatgttc 900
atgcagaaat acccgcacac ccacctggtt cagcaggcta acccgcgtgg ttctgctggt 960
ccgtgctgca ccccgaccaa aatgtctccg atcaacatgc tgtacttcaa cgacaaacag 1020
cagatcatct acggtaaaat cccgggtatg gttgttgacc gctgcggttg ctcttaaccg 1080
gtccggaatt tcgtatggca atgaaagacg gtgagctggt gatatgggat agtgttcacc 1140
<210> 5
<211> 320
<212> PRT
<213> Artifical Sequence
<400> 5
Met Arg Gly Ser His His His His His His Gly Ser Pro Gly Ser Gly
1 5 10 15
Ser Gly Ser Gly Ser Gly Ser Gly Ala Arg Ser Glu Leu Asn Arg Lys
20 25 30
Asn Tyr His Tyr Gln Gln Phe Ile Thr Ala Tyr Glu Asn Leu Leu Arg
35 40 45
Asp Lys Val Glu Asn Asp Ser Ala Glu Pro Gln Thr Phe Thr Ala Asn
50 55 60
Gly Arg Gln Leu Ser Gln Asp Ala Leu Gly Ile Asn Gly Asp Gln Val
65 70 75 80
Trp Thr Tyr Ala Lys Lys Gly Asn Asp Phe Arg Thr Ile Gln Leu Leu
85 90 95
Asn Leu Met Gly Ile Thr Ser Asp Trp Lys Asn Glu Asp Gly Tyr Glu
100 105 110
Asn Asn Lys Thr Pro Asp Glu Gln Thr Asn Leu Leu Val Thr Tyr Pro
115 120 125
Leu Thr Gly Val Ser Met Ala Glu Ala Asp Arg Ile Ala Lys Gln Val
130 135 140
Tyr Leu Thr Ser Pro Asp Asp Trp Leu Gln Ser Ser Met Ile Ser Leu
145 150 155 160
Ala Thr Gln Val Lys Thr Asn Glu Asn Gly Asp Pro Val Leu Tyr Ile
165 170 175
Gln Val Pro Arg Leu Thr Leu Trp Asp Met Ile Tyr Ile Asn Glu Thr
180 185 190
Ile Lys Pro Glu Thr Pro Lys Val Pro Glu Gln Pro Gln His Pro Arg
195 200 205
Ser Gly Ser Gly Ser Gly Leu Asp Cys Asp Glu His Ser Thr Glu Ser
210 215 220
Arg Cys Cys Arg Tyr Pro Leu Thr Val Asp Phe Glu Ala Phe Gly Trp
225 230 235 240
Asp Trp Ile Ile Ala Pro Lys Arg Tyr Lys Ala Asn Tyr Cys Ser Gly
245 250 255
Gln Cys Glu Tyr Met Phe Met Gln Lys Tyr Pro His Thr His Leu Val
260 265 270
Gln Gln Ala Asn Pro Arg Gly Ser Ala Gly Pro Cys Cys Thr Pro Thr
275 280 285
Lys Met Ser Pro Ile Asn Met Leu Tyr Phe Asn Asp Lys Gln Gln Ile
290 295 300
Ile Tyr Gly Lys Ile Pro Gly Met Val Val Asp Arg Cys Gly Cys Ser
305 310 315 320
Claims (4)
1.分子量为35.9kDa的GDF11重组蛋白,所述GDF11重组蛋白包括:具有SEQ ID NO:1的序列的生长分化因子11蛋白的片段、具有SEQ ID NO:2序列的间隔区、具有SEQ ID NO:3的序列的来自变异链球菌(Streptococcus mutans)的α葡聚糖结合结构域;以及编码所述GDF11重组蛋白的核酸具有SEQ ID NO:4的GDF11-GBD基因核苷酸序列,所述GDF11重组蛋白的氨基酸序列如SEQ ID NO:5所示。
2.用于生产在葡聚糖上的如权利要求1所述的GDF11重组蛋白的方法,所述方法包括以下步骤:培养携带pGDF11-GBD质粒的大肠杆菌(E.coli)菌株BL21,破坏细菌细胞,通过亲和结合将作为细胞提取物一部分的GDF11-GBD蛋白与含α-葡聚糖的吸附剂结合,随后进行洗涤以除去未结合的细菌蛋白并回收目标产物。
3.用于增加家畜的肌肉量的注射剂,所述注射剂包含根据权利要求1所述的GDF11重组蛋白,所述GDF11重组蛋白悬浮于能够用于注射的含α-葡聚糖的吸附剂介质的液体佐剂溶液中。
4.用于增加家畜的肌肉量的方法,所述方法包括将含有根据权利要求1所述的GDF11重组蛋白的药物以0.5-150μg指定蛋白/1kg所述家畜体重的剂量进行皮下或肌内注射,所述GDF11重组蛋白悬浮于能够用于注射的含α-葡聚糖的吸附剂的液体佐剂溶液中。
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