CN116440281A - 一种肉毒毒素蛋白组合物 - Google Patents
一种肉毒毒素蛋白组合物 Download PDFInfo
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- CN116440281A CN116440281A CN202210018289.4A CN202210018289A CN116440281A CN 116440281 A CN116440281 A CN 116440281A CN 202210018289 A CN202210018289 A CN 202210018289A CN 116440281 A CN116440281 A CN 116440281A
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- botulinum toxin
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Abstract
本发明公开了一种肉毒毒素蛋白组合物,主要包含肉毒毒素蛋白和蛋白稳定剂组分,可作为液体制剂应用于医疗和美容领域。本发明的肉毒毒素蛋白组合物可以保持肉毒毒素蛋白长期贮存在液体状态下活性稳定。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种肉毒毒素蛋白组合物及其制备方法。
背景技术
天然肉毒杆菌神经毒素(BoNTs)是由梭菌属厌氧肉毒杆菌产生的毒素蛋白,通过阻断神经肌肉接点神经递质乙酰胆碱的突触前释放引起哺乳类动物肌肉麻痹。目前已经发现了七种类型的BoNTs,分别命名为BoNT/A到BoNT/G。BoNTs由于独特的药理学特性,包括对神经系统高度特异性,局部注射有限的扩散,以及作用的可逆性,已经迅速发展成为了一类治疗胆碱能过度兴奋的药物,在医疗和美容领域中具有广泛的应用。
一般说来,治疗用药物活性蛋白通常在液体溶液中配制,特别是用于注射剂。治疗用活性蛋白通常制备成组合物,在商业上以即用溶液形式出售或以用液体溶液重构的冻干形式提供。例如市场上的BoNT/A产品均为真空干燥或冷冻干燥后的固体制剂,在使用时需要医护人员进行复溶,因此需要精确地控制复溶体积。此外,由于不同的治疗目的以及患者间在需用剂量上存在个体差异,每个治疗所需的剂量差别相当大,市场产品所含的药物量在按照厂家要求的体积复溶后,临床医生往往将瓶中的含量的一小部分给药于患者,其余放置冰箱再用。有研究估计,当复溶的BoNT/A在冰箱(约4℃)下贮藏12小时后,其效力损失至少44%,所以一般在实际操作中,建议复溶后4小时内使用,这会导致药品的浪费和患者承担了不必要的经济损失。
此外,由于肉毒毒素使用浓度极低,为了在极低浓度下保持肉毒毒素蛋白质的稳定性,同时避免药物在固态表面的吸附,一般会添加高浓度外源蛋白进行配制。在肉毒毒素配方中大多数使用白蛋白或明胶用作稳定剂,不但会引起免疫反应,并有引入污染源的可能。
发明内容
针对背景技术中提到的技术问题,本发明提供一种肉毒毒素蛋白组合物及其制备方法。
本发明的技术方案如下:
本发明提供一种肉毒毒素蛋白组合物,包括以下组分:
肉毒毒素蛋白和蛋白稳定剂。
所述蛋白稳定剂选自氨基酸或类氨基酸化合物中任一种;
优选的,所述类氨基酸化合物为左旋卡尼汀(别名:维生素Bt,左旋肉碱)。
更优选的,所述左旋卡尼汀的摩尔含量为5-20mM,在一个具体的实施方式中,所述左旋卡尼汀的摩尔含量为10mM。
优选的,所述氨基酸的摩尔含量为5-20mM;在一个具体的实施方式中,所述氨基酸的摩尔含量为10mM。
更优选的,所述氨基酸选自L-组氨酸、L-甘氨酸、L-精氨酸、L-甲硫氨酸、L-组氨酸、L-赖氨酸中的一种或多种。
一般说来,蛋白在低浓度时(<0.1mg/ml)极易降解而失活,本申请的一些氨基酸以及类氨基酸化合物,可以增加蛋白质在特定pH的溶解度,并可提高其稳定性,另外氨基酸及类氨基酸结构化合物除了可以降低表面吸附和保护蛋白质的构象之外,还可以防止蛋白质的变性与聚集,另外,当本发明的蛋白稳定剂为左旋卡尼汀时,与常用的辅料相比,左旋卡尼汀使配方具有低粘度的特点、并且能够减少肉毒毒素蛋白聚集和沉淀,有利于维持肉毒毒素蛋白稳定。
优选的,所述肉毒毒素蛋白选自A型肉毒毒素蛋白、B型肉毒毒素蛋白、C1型肉毒毒素蛋白、C2型肉毒毒素蛋白、D型肉毒毒素蛋白、E型肉毒毒素蛋白、F型肉毒毒素蛋白或G型肉毒毒素蛋白中的任一种;更优选的,所述肉毒毒素蛋白为A型肉毒毒素蛋白。
更优选的,所述肉毒毒素为重组肉毒毒素。
更为优选的,所述重组肉毒毒素蛋白由单链多肽经蛋白酶切割后形成多肽组成的至少一个二聚体结构;
所述的单链多肽包含:
(I)第一多肽片段,所述第一多肽片段包含:
(a)标签蛋白,
(b)包含第一蛋白酶切割位点的结构区;
(c)连接短肽,
(II)第二多肽片段,所述第二多肽片段包含:
(d)第一功能氨基酸结构区,其包含金属离子依赖的蛋白酶活性域;
(e)包含第二蛋白酶切割位点的结构区;
(f)第二功能氨基酸结构区,其包含可与靶细胞表面受体结合的受体结合域和/或可以介导多肽跨囊泡膜转移的易位域。
术语“标签蛋白”是指可以与特定的配基结合的一类蛋白分子。
优选的,所述的标签蛋白选自本领域技术人员已知的标签蛋白或者经过计算机程序设计的标签蛋白,所述的标签蛋白能够与已知底物特异结合。
更优选的,所述的标签蛋白选自但不限于以下蛋白:谷胱甘肽S-转移酶(GSTs)、C-myc、几丁质结合结构域、麦芽糖结合蛋白(MBP)、SUMO异源亲和部分、单克隆抗体或蛋白A、链霉亲和素结合蛋白(SBP)、纤维素结合结构域、钙调蛋白结合肽、S标签、Strep标签II、FLA、蛋白A、蛋白G、组氨酸亲和标签(HAT)、多聚组氨酸。
优选的,所述的“标签蛋白”可以增加毒素多肽前体的在宿主中的可溶性。
优选的,所述的“标签蛋白”使得毒素多肽前体以可溶的方式存在于宿主细胞中。
在一个具体实施例中,所述的标签蛋白位于单链多肽的N端。
在一个具体实施例中,所述的标签蛋白为谷胱甘肽s-转移酶(GSTs),更优选的,所述谷胱甘肽s-转移酶的氨基酸序列如SEQ ID NO:2所示。
优选的,所述的第一蛋白酶切割位点和第二蛋白酶切割位点均不能被人蛋白酶或表达所述单链多肽的宿主细胞自身产生的蛋白酶切割。
更优选的,所述的第一蛋白酶切割位点和第二蛋白酶切割位点相同或不同。
所述的第一蛋白酶切割位点和第二蛋白酶切割位点不被表达时的宿主细胞或使用时机体内源性的蛋白酶识别和切割。
更优选的,所述的特定的蛋白酶选自但不限于以下蛋白酶的一种或两种的组合:非人肠激酶、烟草蚀刻病毒蛋白酶、来源于枯草芽孢杆菌的蛋白酶、来源于解淀粉芽孢杆菌的蛋白酶、来源于鼻病毒的蛋白酶、木瓜蛋白酶、昆虫木瓜蛋白酶的同源物或甲壳动物木瓜蛋白酶的同源物。
在一个具体实施例中,所述的特异地识别第一蛋白酶和所述的特异地识别第二蛋白酶切割位点的蛋白酶均为来源于鼻病毒的蛋白酶。
优选的,第二酶切位点嵌入、部分替换或全部替换第一功能肽段和第二功能肽段之间的天然存在的环状区域。所述的嵌入是指插入在所述的环状区域的某两个氨基酸之间;所述的部分替换是指所述的第二酶切位点替换了所述的环状区域的部分氨基酸序列;所述的完全替换是指天然的环状区域的氨基酸序列完全被第二酶切位点所取代。
更优选的,所述的包含第一蛋白酶切割位点的结构区和包含第二蛋白酶切割位点的结构区选自但不限于以下酶切位点的一种或两种的组合:DDDDK、EXXYXQS/G、HY、YH或LEVLFQGP。
在一个具有实施例中,所述的包含第一蛋白酶切割位点的结构区和包含第二蛋白酶切割位点的结构区均为LEVLFQGP,切割位点在Q-G之间。
优选的,所述的连接短肽不超过5个氨基酸。
优选的,所述连接短肽能够使第一蛋白酶切割位点更容易被其蛋白酶识别或结合。
更优选的,所述的连接短肽不影响单链多肽的功能。
更优选的,所述的第一蛋白酶切割位点被切开后,保留在第二多肽片段N端的连接短肽不会影响第二多肽片段的功能。
更优选的,所述的连接短肽GS部分不超过5个氨基酸残基,更优选的,所述的连接短肽选自甘氨酸-丝氨酸(Glycine-Serine,简称GS)短肽,GGS,GGGS,GGGGS,GSGS,GGSGS,GSGGS,GGSGS,GGGSS等连接短肽。
在一个具体实施例中,所述的包含第一蛋白酶切割位点的结构区和连接短肽的氨基酸序列为LEVLFQGPLGS。
优选的,所述的金属离子依赖的蛋白酶活性域为Zn2+依赖的蛋白酶活性域。
优选的,所述的第一功能氨基酸结构区和/或第二功能氨基酸结构区由天然序列和/或人工合成的序列编码。更优选的,所述的单链多肽的第一功能氨基酸结构区包含梭菌毒素轻链的Zn2+蛋白酶活性域。
优选的,所述的第二功能氨基酸结构区中的能够结合人体细胞表面抗原的受体结合域的靶细胞是指存在SNARE复合体的靶细胞。例如:神经细胞、胰腺细胞或其他存在SNARE复合体的细胞。
更优选的,所述的第二功能氨基酸结构区中的靶细胞是指人神经细胞或胰腺细胞,所述的受体结合域为能够特定结合人神经细胞或胰腺细胞的受体结合域。
更优选的,所述的第二功能氨基酸结构区的受体结合域为梭菌毒素的重链的细胞表面抗原结合结构域,所述的第二功能氨基酸结构区的介导多肽跨囊泡膜转移的易位域为介导梭菌毒素跨囊泡膜转移的结构域。
更优选的,所述的梭菌毒素为肉毒杆菌毒素或破伤风毒素。
更优选的,所述的肉毒杆菌毒素选自现有技术已知的血清型BoNT/A-BoNT/H以及它们的衍生物中的任意一种。
更优选的,所述的梭菌毒素选自破伤风毒素或其衍生物中的任意一种。
更优选的,所述的第一功能氨基酸结构区包含BoNT/A、BoNT/B、BoNT/C、BoNT/D、BoNT/E、BoNT/F、BoNT/G、BoNT/H或破伤风毒素的轻链的部分或全部。
更优选的,所述的第二功能氨基酸结构区包含BoNT/A、BoNT/B、BoNT/C、BoNT/D、BoNT/E、BoNT/F、BoNT/G、BoNT/H或破伤风毒素的重链的部分或全部。
在一个具体实施例中,所述的第一功能氨基酸结构区为BoNT-/A的轻链,所述的第二功能氨基酸结构区为BoNT-/A的重链。
更优选的,所述的第一功能氨基酸结构区和第二功能氨基酸结构区可以来自不同的血清型。可以是上述血清型的任意组合,例如,所述的第一功能氨基酸结构区衍生自BoNT-/A的轻链,所述的第二功能氨基酸结构区衍生自BoNT-/B、BoNT/C、BoNT/D、BoNT/E、BoNT/F或BoNT/G的重链,或者,所述的第一功能氨基酸结构区衍生自BoNT/B、BoNT/C、BoNT/D、BoNT/E、BoNT/F或BoNT/G的轻链,所述的第二功能氨基酸结构区衍生自BoNT/A的重链等。
更优选的,所述的第二多肽片段的氨基酸序列包含SEQ ID NO:7所示的片段。
在一个具体实施例中,所述的单链多肽从N端开始依次包含:谷胱甘肽S-转移酶、LEVLFQGPLGS、BoNT/A的轻链、LEVLFQGP和BoNT/A的重链。
更优选的,所述的单链多肽的氨基酸序列如SEQ ID NO:11所示。
更优选的,重组A型肉毒毒素蛋白通过将单链多肽的经第一蛋白酶切割去除标签蛋白,和经第二蛋白酶切割后第一功能氨基酸结构区和第二功能氨基酸结构区形成至少一个二聚体来制备。
优选的,所述第一功能氨基酸结构区和第二功能氨基酸结构区经过二硫键连接成二聚体结构。
本发明的重组A型肉毒毒素蛋白,由特定的单链多肽形成,其中,所涉及的单链多肽具有特定的结构,该结构的单链多肽具有特异性强、毒性低的特点。具体的,从特异性强的角度来说,该单链多肽中的标签蛋白其能够与特异的配体结合,再经过与配体的脱离,使得与标签蛋白共表达的分子更易于从不同的多肽或蛋白产物中被选择出来,在制备过程中,可以显著的提升产品的纯度,使得产品得率更高、纯度更高;从毒性低的角度来说,该单链多肽中的标签蛋白使得多肽中第一功能氨基酸结构区的蛋白酶结构域不能发挥蛋白酶的功能,通过将第一功能氨基酸结构区和第二功能氨基酸结构区之间的天然酶切位点替换为仅特定的酶才可以识别的位点,从而使得该单链多肽的分子活性(神经毒性)降低至天然毒素的万分之一以下,有效的降低了毒性,由于其毒性被大幅降低,从而提高了生产过程中的安全性,使得整个工业化生产更易于进行。也就是说,本发明所涉及到重组肉毒毒素蛋白中的单链多肽,由于得率更高、纯度更高以及安全性也更高,相比于现有技术,更易于进行工业化的生产和纯化操作。
优选的,所述组合物还包括增溶剂和/或盐类化合物。
更优选的,所述增溶剂的体积百分比浓度为0.05%-0.2%。
更优选的,所述盐类的质量百分比浓度为0.9%。
更优选的,所述增溶剂选自吐温类、司盘类、十二烷基硫酸钠;
更优选的,所述吐温类选自吐温20、吐温40、吐温60、或吐温80中的一种或多种;
进一步优选的,所述司盘类选自司盘20、司盘40、司盘60、司盘80、或司盘85中的一种或多种;
在一个具体的实施方式中,所述增溶剂为吐温80。
优选的,所述盐类选自无机盐或有机盐中任一种;
更优选的,所述无机盐选自氯化钠、磷酸钠、硫酸镁、乙酸钠、丙酸钠和磷酸钾中的一种或多种;
进一步优选的,所述有机盐选自乳酸钠、琥珀酸钠中的一种或多种;
在一个具体的实施方式中,所述无机盐为氯化钠。
优选的,所述组合物包括肉毒毒素蛋白、左旋卡尼汀、吐温80、氯化钠;
或,
所述组合物包括肉毒毒素蛋白、氨基酸、吐温80、氯化钠。
更优选的,所述左旋卡尼汀的摩尔含量为5-20mM,优选为10mM;
或,所述氨基酸的摩尔含量为5-20mM;优选为10mM。
更优选的,所述吐温80的体积百分比浓度为0.05%-0.2%。
在一个具体的实施方式中,所述吐温80的体积百分比浓度为0.1%。
更优选的,所述氯化钠的质量百分比浓度为0.9%。
所述组合物为液体制剂。
本发明还提供肉毒毒素蛋白组合物的制备方法,所述制备方法包括将各组分混合的步骤。
优选的,上述制备方法的步骤包括:
(a)制备、纯化肉毒毒素蛋白;
(b)向所述肉毒毒素蛋白中加入蛋白稳定剂水。
所述水为注射用水。
更优选的,所述步骤(b)中还包括加入增溶剂和/或盐类。
其中,所述肉毒毒素蛋白、蛋白稳定剂、增溶剂和/或盐类如上所限定。
在一个具体的实施方式中,所述制备方法包括:
(a)制备、纯化重组A型肉毒毒素蛋白;
(b)向所述重组A型肉毒毒素蛋白中加入蛋白稳定剂水、吐温80和氯化钠、水。
所述水为注射用水。
本发明还提供了上述肉毒毒素蛋白组合物在制备用于预防和/或治疗与支配肌肉或外分泌腺的胆碱能神经相关的疾病、医学美容的药物中的应用。
所述与支配肌肉或外分泌腺的胆碱能神经相关的疾病或病症包括:与胆碱能神经支配相关的肌肉或外分泌腺过度活跃的示例性疾病或病症包括,例如弗雷综合征、鳄鱼泪综合征、腋下多汗症、足底多汗症、头颈多汗症、身体多汗症、鼻漏、帕金森氏病、肌萎缩侧索硬化、多涎、垂涎、流涎、痉挛状况、腭肌阵挛、肌阵挛、肌纤维颤搐、僵直、良性肌肉痉挛、遗传性下巴颤抖、反常性下颌肌肉活动、半侧咀嚼肌痉挛、肥大型鳃肌病、嚼肌肥大、胫骨前肌肥大、眼球震颤、振动幻视、核上凝视麻痹、持续状态部分性癫痫、痉挛性斜颈手术计划、展肌声带麻痹、顽固性突变性发音障碍、上食道括约肌功能障碍、声带肉芽肿、口吃、抽动秽语综合征、中耳肌阵挛、保护性喉闭合、喉切除术后言语失败、保护性上睑下垂、睑内翻、奥狄氏括约肌功能障碍、假性食道弛缓不能、非失弛缓性食道运动障碍、阴道痉挛、术后卧床、震颤、膀胱功能障碍、半面痉挛、神经支配恢复术运动障碍、僵人综合征、破伤风、前列腺增生、肥胖治疗、婴儿大脑性麻痹、失弛缓症和肛裂。
所述医学美容包括平滑或预防皱纹、瘦脸、疤痕修复。
所述皱纹可被视为皮肤中的褶皱、嵴或褶痕。优选人类的面部中可见的皱纹。皱纹的例子包括泪沟、眉间纹、鱼尾纹、颊连合处纹、下颌纹、口周皱纹、颊褶皱、木偶纹、唇纹、前额皱纹、皱眉纹、兔纹、鼻唇沟、眼下皱纹和下巴褶皱。
与现有技术相比,本发明具有如下有益效果:
(1)本发明提供了一种稳定的肉毒毒素蛋白组合物。其组合物中使用氨基酸或类氨基酸取代了人源蛋白(例如人血白蛋白),杜绝了人源病毒的威胁,同时配合吐温80防止吸附,能在标准冰箱(约4℃)内以液体状态稳定贮藏1年或更长,能在室温(25℃)以液体状态稳定贮藏6个月或更长。
(2)本发明提供一种重组肉毒毒素蛋白组合物,采用特定单链多肽制备的高纯度重组A型肉毒毒素蛋白,能够提升制剂中A型肉毒毒素蛋白的纯度,避免了从肉毒杆菌提取A型肉毒毒素所包含的非活性肉毒杆菌蛋白摄入人体可能产生的免疫风险,为扩大重组A型肉毒毒素蛋白的应用范围提供了新的选择。
(3)本发明的肉毒毒素蛋白组合物作为液体制剂使用时,增加了临床使用方便性,改善了冻干或真空产品复溶后通常保存时间较短,易造成使用浪费以及复溶过程中人为污染或复溶不准确等缺陷。
附图说明
图1:GSTs-BoNT/A初步纯化和进一步去除GSTs标签的SDS-PAGE结果,其中第1泳道为经过GSTs亲和层析柱初步纯化得到的GSTs-BoNT/A,第2泳道为初步纯化的蛋白经过Rinovirus 3C Protease的酶切去除GSTs标签蛋白得到切除GSTs后的BoNT/A。
图2:切除了GSTs标签的产物经过离子交换柱进一步纯化得到高纯度的BoNT/A蛋白的SDS-PAGE结果。
图3:BoNT/A在还原条件下双链解离的验证结果。
具体实施方式
除非另有定义,本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
本发明中,术语“U”是指效价单位,药剂学上使用的(表示)生物学能力的多样的单位。因为这些药物的化学成分不恒定或至今还不能用理化方法检定其质量规格,往往采用生物实验方法并与标准品加以比较来检定其效价。通过这种生物检定,具有一定生物效能的最小效价单元就叫“单位”(U);经由国际协商规定出的标准单位,称为“国际单位”(IU);
术语“BoNT/A”是指A型肉毒毒素蛋白;
术语“标签蛋白”是指利用DNA体外重组技术,与目的蛋白一起融合表达的一种多肽或者蛋白,以便于目的蛋白的表达、检测。
术语“人血清白蛋白”(Human serum albumin),简称HSA,是指人血浆中的蛋白质,在体液中HSA可以运输脂肪酸、胆色素、氨基酸、类固醇激素、金属离子和许多治疗分子等:同时维持血液正常的渗透压。在临床上HSA可用于治疗休克与烧伤,用于补充因手术、意外事故或大出血所致的血液丢失,也可以作为血浆增容剂。
术语“二聚体结构”是指为由两个分子组合而成的高分子配合物,常以非共价键键结。
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述。显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实验例1重组A型肉毒毒素蛋白的制备
具体分为以下8个步骤:
1、设计和构建编码经修饰的肉毒毒素的单链多肽的核酸分子:
核酸分子从5’端起依次包含:
(a)编码谷胱甘肽s-转移酶的核苷酸序列如SEQ ID NO:1所示,其编码的谷胱甘肽s-转移酶的氨基酸序列如SEQ ID NO:2所示;
(b)编码第一蛋白酶切割位点的核苷酸序列如SEQ ID NO:3所示,其编码的氨基酸序列如SEQ ID NO:4所示;
(c)编码GS连接短肽的核苷酸序列如SEQ ID NO:5所示,为GGATCC;
(d)编码第二多肽片段的核苷酸序列,其包含BoNT/A轻链、第二蛋白酶切割位点和BoNT/A重链的核苷酸序列,如SEQ ID NO:6所示,其编码的氨基酸序列如SEQ ID NO:7所示;其中,编码第二蛋白酶切割位点的核苷酸序列如SEQ ID NO:8所示,其编码的氨基酸序列如SEQ ID NO:9所示;
BoNT/A轻链和BoNT/A重链之间也可以不存在天然的环状区域,例如去除轻链和重链之间的KTKSLDKGYNK连接序列,以减少非特异性蛋白酶切割。
编码单链多肽的核苷酸序列如SEQ ID NO:10所示,其编码的单链多肽的氨基酸序列如SEQ ID NO:11所示。
2、构建包含步骤1序列的核酸分子的质粒
在上述人工合成基因工程优化后的GSTs-BoNT/A,两端合成加入NdeI和NotI酶切位点,经过NdeI和NotI 37摄氏度酶切(New England Biolabs),使用QIquick gelextraction kit(Qiagen)纯化,使用T4 DNA ligase(NEB)插入pET28a(Novagen)质粒载体中的NdeI和NotI的位点。
3、转染步骤2构建的质粒到宿主细胞
(a)感受态细胞的制备:取一管大肠杆菌细胞E.coli BL21 DE3(New EnglandBiolabs),接种至含有3ml LB培养液的试管中,37℃振荡培养过夜。次日取菌液0.5ml接种至含有50ml LB培养基的250ml烧瓶中,37℃剧烈震荡培养约3-5小时(250rpm),当菌落600nm OD值达到0.3-0.4时,将烧瓶取出放置冰上10-15分钟。在无菌条件下把菌液倒入50ml离心管中。4℃,1000g离心10分钟。弃上清,收集加10ml 0.1M的CaCl2到离心管中,振荡混匀,悬浮菌体,冰浴30分钟,4℃,1000g离心10分钟,弃上清,收集加4ml冰预冷的0.1M的CaCl2,重悬浮菌体。每管0.2ml分装,至4℃保存备用,24小时内使用,其余保存于-70℃的低温冰箱中。
(b)转染:适量DNA(ng)和感受态大肠杆菌混合放置冰浴15分钟,42℃热击30秒,放置冰浴5分钟,放入SOC培养基250rpm摇晃1小时,涂抹在有抗生素的平板上,37℃隔夜培养。
4、培养宿主细胞和诱导表达单链多肽
培养基的组分和配比:11.8g/L胰蛋白胨、23.6g/L酵母提取物、9.4g/L K2HPO4、2.2g/L KH2PO4、4ml/L甘油。
培养条件:37℃隔夜250rpm震荡培养细胞。
诱导表达:当大肠杆菌生长到OD600=1的时候,加入1mM IPTG诱导表达在25℃表达5个小时。OD600可以选用0.2-1.5,温度可以选用37℃到10℃,表达时间可以是5-16个小时。
收获细胞:3000rpm 30分钟离心收集大肠杆菌。
5、单链多肽表达水平的鉴定
使用金斯瑞谷胱甘肽纯化树脂制备一根直径1厘米,高1厘米的谷胱甘肽纯化树脂层析柱,缓慢地倾倒25毫升裂解液到层析柱上层,注意不要冲起树脂,经过一小时缓慢过柱吸附裂解液中的GSTs-BoNT/A。按照常规方法洗脱获得GSTs-BoNT/A。
常规方法如下:使用20倍柱体积的磷酸缓冲液洗涤层析柱,用10倍柱体积的新鲜制备的10mM谷胱甘肽洗脱缓冲液(0.154g还原的谷胱甘肽溶解在50ml50mM Tris-HCl(pH8.0))进行GSTs-BoNT/A洗脱,使用280nm处的吸光度读数监控融合蛋白的洗脱。洗脱后的蛋白在Rinovirus 3C Proteas作用下切除GSTs标签蛋白。
取去除GSTs标签蛋白之前的产物和之后的产物进行常规的SDS-PAGE实验,如图1所示,与没有标签蛋白去除的第1泳道相比,在Rinovirus 3C Protease的作用下,第1泳道的GSTs标签蛋白被切除,得到没有GSTs的BoNT/A分子。
GSTs-BoNT/A在总蛋白水平中所占的比例的测定:使用4-12%SDS-PAGE(Biorad)对纯化的GSTs-BoNT/A在200伏电压下电泳分离,175kd分子量主要条带是GSTs-BoNT/A。
6、标签蛋白的去除以及提纯
对将步骤5的产物进行GSTs标签蛋白的去除和有毒多肽的提纯:
用金斯瑞3C酶处理重新吸附在谷胱甘肽纯化树脂层析柱上的GSTs-BoNT/A,在3C酶的作用下,GSTs和BoNT/A之间的第一酶切位点被断开,GSTs脱离,同时BoNT/A的轻链和重链之间的第二酶切位点被断开。
以磷酸缓冲液处理谷胱甘肽纯化树脂层析柱,GSTs标签蛋白留在柱子上,被去除掉,而BoNT/A的轻链和重链被磷酸缓冲液洗脱下来。
取去除了GSTs的产物进行常规的SDS-PAGE实验,如图2所示,得到的条带中不再有GSTs标签蛋白,说明GSTs标签蛋白已经被完全去除。使用SDS-PAGE扫描图片,根据条带灰色密度来计算所得BoNT/A为90%纯度以上。
采用GSS、GSGS、GGSGS多肽代替链接短肽GS部分,其效果和GS相似,标签蛋白可以很好得暴露,从而能被完全切除。
7、二聚体BoNT/A的双链在还原条件下的解离
将步骤6的产物进行还原实验:
使用100mM的二硫苏糖醇,在100摄氏度下处理样品五分钟,使样品还原,样品经过4-12%SDS-PAGE(Biorad)200伏电压电泳分离,分离出重链和轻链。如图3所示,将步骤6得到的产物在还原条件下进行还原,得到的产物进行常规的SDS-PAGE实验,得到两条不同的条带,分子量分别在100Kda和50Kda,证明步骤6形成的产物是以二硫键链接两个肽段的二聚体结构。
8、GSTs-BoNT/A的毒性试验
用步骤5获得的GSTs-BoNT/A经小鼠腹腔注射的LD50在45ng-450ng之间;考虑到所注射的肉毒毒素蛋白纯度,折算的LD50在22.5ng-225ng之间,中间值为123.75ng。用步骤5获得的BoNT/A经小鼠腹腔注射的LD50在0.02ng–0.05ng之间。考虑到所注射的肉毒毒素蛋白纯度,折算的LD50在0.006ng-0.015ng之间,中间值为0.0105ng(见表1)。
表1:GSTs-BoNT/A和BoNT/A分子在小鼠生物毒性实验中的毒性比较
GSTs-BoNT/A具有肉毒毒素的活性,经小鼠腹腔注射后,其半数致死量(LD50)大约比BoNT/A的蛋白LD50高11786倍,表明GSTs-BoNT/A重组蛋白毒素多肽前体分子活性弱于最终产品BoNT/A大约11786倍。这个实验证明,GSTs-BoNT/A重组蛋白毒素多肽前体分子具有肉毒毒素的活性。由于肉毒毒素的超高毒性,因此生产过程中,在未对前体分子作活化处理前就需要高度安全操作防护。
实施例2重组A型肉毒毒素蛋白组合物的优化
通过小鼠半数致死量评估肉毒毒素蛋白(实施例1制备)的活性,并以小鼠单位(U)显示,一个单位定义为杀死小鼠总体数量50%所需的腹腔注射重组A型肉毒毒素蛋白量。
一、动物实验过程:
1、选种分组:
选取CD-1品种的成年小鼠,分组,称重、编号、保证每组小鼠数量相等,体重相近。
2、给药:
表2中不同配方制剂给药,给药过程中,腹腔单次注射给予CD-1小鼠不同制剂配方重组A型肉毒毒素蛋白制剂均为0.5mL。经小鼠腹腔注射药的重组A型肉毒毒素蛋白量为2XLD50(2U)。
3、观察:
试验开始前,每只动物称量一次体重(第一天给药前)并记录,给药后,每24h称量一次体重,在给药后24h(±1h)、48h(±1h)、72h(±1h)、96h(±1h),检查死亡率。
二、实验结果
选取表2中所列的含有2U肉毒毒素的各组分配方(1-4)注射小鼠腹腔,观察各制剂储存在4℃条件下0至211天后2U肉毒毒素对每组小鼠的致死率,实验过程同上述动物实验,实验结果如表2所示。
表2.各组分配方制剂储存不同时间后的活性测定
从表2的结果中可以看出,表中4个配方在4℃条件下放置0至211天后,重组A型肉毒毒素对小鼠的致死作用(药物活性)没有减弱,仍然保持重组A型肉毒毒素蛋白在放置4℃保存前的生物活性,证明本发明所选择的配方能够维持重组A型肉毒毒素的长期稳定性。
选取表2中两个制剂测定了重组A型肉毒毒素储存在4℃ 44,75和211天后的小鼠半数致死量(LD50)。实验结果见表3.
表3.重组A型肉毒毒素在4℃保存44,75和211天后的小鼠LD50测定值
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从表3中可以看出,配方1在4℃放置211天后,能保持重组A型肉毒毒素蛋白的活性,配方2在4℃放置70天后,能保持重组A型肉毒毒素蛋白的活性,经过多剂量-活性关系计算的重组A型肉毒毒素的小鼠半数致死量(LD50)经过4℃分别放置44,70和211天后没有明显变化,半数致死量仍然保持基本不变,充分证明本发明的制剂配方能够有效维持重组A型肉毒毒素的生物活性长期稳定。
本发明采用重组肉毒毒素,使用氨基酸或类氨基酸化合物作为蛋白稳定剂,可以在低温条件(如4℃下)长时间储存(如4℃下储存70天以上),本发明的制剂配方也可保持天然肉毒素蛋白(A型肉毒毒素蛋白、B型肉毒毒素蛋白、C1型肉毒毒素蛋白、C2型肉毒毒素蛋白、D型肉毒毒素蛋白、E型肉毒毒素蛋白)的活性。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明。凡在本发明的精神和原则之内所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
本文描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中,仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
序列表
<110> 重庆誉颜制药有限公司
<120> 一种肉毒毒素蛋白组合物
<130> 1
<160> 11
<170> SIPOSequenceListing 1.0
<210> 1
<211> 654
<212> DNA
<213> Artificial Sequence
<400> 1
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaa 654
<210> 2
<211> 218
<212> PRT
<213> Artificial Sequence
<400> 2
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys
210 215
<210> 3
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 3
ctggaagttc tgttccaggg gccc 24
<210> 4
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 4
Leu Glu Val Leu Phe Gln Gly Pro
1 5
<210> 5
<211> 6
<212> DNA
<213> Artificial Sequence
<400> 5
ggatcc 6
<210> 6
<211> 3882
<212> DNA
<213> Artificial Sequence
<400> 6
atgcctttcg ttaacaaaca gtttaactat aaggacccgg ttaacggtgt ggatattgca 60
tacattaaga tccctaacgc tggtcagatg cagccggtga aagcattcaa gatccacaat 120
aagatttggg tgatcccgga acgcgatacc tttaccaacc cggaagaagg cgatctgaac 180
ccccctccgg aggccaagca agttcccgtt agctattacg acagtaccta tttaagcacc 240
gataatgaga aagataacta tctgaagggt gttaccaaac tgttcgagcg catctacagc 300
acagacttag gccgcatgct gctgaccagt atcgttcgtg gtattccgtt ctggggcggc 360
agtaccatcg acaccgagct gaaagtgatc gacaccaatt gcattaacgt gatccagccc 420
gatggcagct atcgtagcga agagctgaat ctggttatca tcggccctag tgccgacatt 480
attcaattcg agtgtaaaag cttcggccat gaggtgctga atttaacccg taatggctat 540
ggcagtaccc agtacatccg cttcagcccg gattttacct tcggcttcga ggaatcttta 600
gaagtggata ccaatccgct gctgggcgcc ggcaaatttg caacagaccc cgctgttact 660
ttagcccatg agctgattca tgctggtcat cgtctgtacg gcatcgccat taacccgaac 720
cgtgtgttta aggttaacac caacgcctat tatgaaatga gtggtttaga ggtgagcttc 780
gaggagctgc gtacctttgg tggccatgat gccaagttca tcgatagtct gcaagaaaac 840
gagtttcgtc tgtattatta caacaagttc aaagatatcg caagcacctt aaataaagcc 900
aagagcatcg ttggcaccac cgcctcttta caatatatga aaaacgtttt caaggagaaa 960
tatctgctga gcgaggacac cagtggtaaa tttagtgttg acaaactgaa gttcgataaa 1020
ctgtataaga tgctgaccga gatctatacc gaagacaatt tcgtgaaatt ttttaaagtt 1080
ctgaatcgca aaacatattt aaacttcgac aaagcagtgt ttaaaatcaa catcgttccg 1140
aaggttaatt acacaatcta cgatggcttc aatttacgca acaccaattt agccgcaaac 1200
ttcaacggcc aaaataccga gatcaataac atgaatttca ccaaactgaa aaactttact 1260
ggtttatttg agttctacaa actgctgtgc gtgcgtggca ttatcaccag tttagaagtg 1320
ctgtttcaag gtccggcctt aaacgatctg tgtattaaag ttaacaattg ggatctgttt 1380
ttcagcccta gcgaggacaa ttttaccaac gatttaaaca aaggcgagga gatcaccagc 1440
gataccaata ttgaggccgc agaggagaat atcagtctgg atttaatcca gcaatattat 1500
ctgaccttta attttgacaa tgagccggag aacattagta tcgaaaattt aagtagcgac 1560
atcattggtc agctggagct gatgccgaac attgagcgct tcccgaatgg caaaaagtat 1620
gaattagata agtacaccat gtttcactat ttacgcgccc aagaatttga acacggtaaa 1680
agccgtattg ccttaaccaa cagcgtgaat gaagcactgc tgaacccgag ccgcgtgtat 1740
acctttttca gtagtgacta tgttaagaag gtgaataagg ccaccgaagc cgccatgttc 1800
ttaggctggg tggagcagct ggtgtatgat ttcaccgatg agaccagcga ggtgagcacc 1860
acagataaaa tcgcagatat tacaattatt attccgtaca tcggcccggc tttaaatatc 1920
ggtaacatgc tgtacaaaga tgatttcgtg ggcgctttaa tctttagcgg tgccgttatt 1980
ctgttagaat tcattcccga aattgcaatc ccggtgctgg gcacctttgc tttagttagc 2040
tatatcgcaa ataaagtgtt aaccgttcag accattgaca atgctttaag caagcgtaat 2100
gaaaagtggg atgaggttta taaatacatc gttacaaatt ggttagccaa agtgaacacc 2160
cagattgatt taatccgtaa gaaaatgaaa gaagccttag agaatcaagc tgaggccaca 2220
aaagcaatta tcaattacca gtacaatcag tataccgaag aagaaaagaa caatatcaac 2280
tttaatattg atgatttaag cagcaagctg aacgaaagca ttaataaagc catgattaat 2340
attaacaagt ttttaaacca gtgcagcgtg agctatttaa tgaacagcat gatcccttac 2400
ggtgtgaagc gtctggaaga tttcgatgcc tctttaaaag acgcactgtt aaagtatatt 2460
tatgacaatc gcggcacact gatcggtcaa gttgatcgtc tgaaagataa agttaataac 2520
acattaagca cagacattcc tttccagctg agtaaatacg tggacaatca acgtctgctg 2580
agcaccttta ccgaatacat taaaaacatt attaacacca gcattctgaa tttacgctac 2640
gagagcaacc atttaattga tctgagccgt tacgccagca agatcaatat cggtagcaag 2700
gttaacttcg acccgattga caaaaaccag atccagttat tcaatttaga gagtagtaag 2760
attgaggtta ttttaaaaaa cgccatcgtt tataacagca tgtacgaaaa ttttagcaca 2820
agcttttgga ttcgtatccc gaagtatttc aatagcatct ctttaaataa tgaatacaca 2880
atcattaatt gcatggaaaa caacagcggc tggaaggtgt ctttaaacta cggtgagatc 2940
atctggactt tacaagatac ccaagaaatc aagcagcgcg ttgtgttcaa atatagtcag 3000
atgatcaaca ttagtgacta tattaaccgc tggatttttg tgaccatcac aaataaccgt 3060
ttaaacaaca gcaaaattta tattaacggt cgtctgattg accagaagcc gattagcaat 3120
ttaggtaata tccatgccag caacaacatt atgttcaaac tggatggttg tcgcgatacc 3180
catcgctaca tctggattaa gtactttaac ttattcgaca aagaactgaa tgaaaaggag 3240
atcaaggact tatatgataa tcaaagcaat agcggcattt taaaagactt ttggggtgac 3300
tatctgcagt atgacaaacc ttactatatg ctgaacttat atgacccgaa caaatacgtt 3360
gacgtgaaca atgtgggtat tcgtggctac atgtatctga aaggcccgcg cggcagtgtt 3420
atgaccacaa atatttattt aaacagctct ttatatcgtg gcaccaagtt tatcatcaag 3480
aagtacgcaa gcggcaataa agacaatatt gtgcgtaaca acgatcgtgt gtacatcaac 3540
gttgtggtga agaacaaaga gtatcgttta gccaccaatg ccagccaagc tggtgtggaa 3600
aaaattttaa gcgcactgga gatccccgat gtgggcaatt taagtcaagt tgttgtgatg 3660
aaaagtaaga atgatcaagg catcaccaac aaatgtaaga tgaatttaca agacaataac 3720
ggcaatgaca ttggttttat tggtttccat cagttcaaca atatcgcaaa gctggtggcc 3780
agcaactggt acaaccgtca gatcgaacgt agcagccgta ctttaggttg cagctgggaa 3840
tttattccgg tggatgatgg ttggggtgag cgccctttat aa 3882
<210> 7
<211> 1293
<212> PRT
<213> Artificial Sequence
<400> 7
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Ala Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Ile Thr Ser Leu Glu Val Leu Phe Gln Gly Pro Ala Leu Asn
435 440 445
Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe Ser Pro Ser
450 455 460
Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu Ile Thr Ser
465 470 475 480
Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu Asp Leu Ile
485 490 495
Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro Glu Asn Ile
500 505 510
Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu Glu Leu Met
515 520 525
Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu Leu Asp Lys
530 535 540
Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu His Gly Lys
545 550 555 560
Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu Leu Asn Pro
565 570 575
Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys Lys Val Asn
580 585 590
Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu Gln Leu Val
595 600 605
Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr Asp Lys Ile
610 615 620
Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile
625 630 635 640
Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu Ile Phe Ser
645 650 655
Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala Ile Pro Val
660 665 670
Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys Val Leu Thr
675 680 685
Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu Lys Trp Asp
690 695 700
Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys Val Asn Thr
705 710 715 720
Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu Glu Asn Gln
725 730 735
Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn Gln Tyr Thr
740 745 750
Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp Leu Ser Ser
755 760 765
Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile Asn Lys Phe
770 775 780
Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met Ile Pro Tyr
785 790 795 800
Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys Asp Ala Leu
805 810 815
Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly Gln Val Asp
820 825 830
Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp Ile Pro Phe
835 840 845
Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser Thr Phe Thr
850 855 860
Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn Leu Arg Tyr
865 870 875 880
Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser Lys Ile Asn
885 890 895
Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn Gln Ile Gln
900 905 910
Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu Lys Asn Ala
915 920 925
Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser Phe Trp Ile
930 935 940
Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn Glu Tyr Thr
945 950 955 960
Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val Ser Leu Asn
965 970 975
Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu Ile Lys Gln
980 985 990
Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser Asp Tyr Ile
995 1000 1005
Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu Asn Asn Ser
1010 1015 1020
Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro Ile Ser Asn
1025 1030 1035 1040
Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys Leu Asp Gly
1045 1050 1055
Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr Phe Asn Leu Phe
1060 1065 1070
Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp Leu Tyr Asp Asn Gln
1075 1080 1085
Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp Gly Asp Tyr Leu Gln Tyr
1090 1095 1100
Asp Lys Pro Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val
1105 1110 1115 1120
Asp Val Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro
1125 1130 1135
Arg Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr
1140 1145 1150
Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp
1155 1160 1165
Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys
1170 1175 1180
Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu
1185 1190 1195 1200
Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser Gln
1205 1210 1215
Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn Lys Cys
1220 1225 1230
Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly Phe Ile Gly
1235 1240 1245
Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser Asn Trp Tyr
1250 1255 1260
Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys Ser Trp Glu
1265 1270 1275 1280
Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu
1285 1290
<210> 8
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 8
ttagaagtgc tgtttcaagg tccg 24
<210> 9
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 9
Leu Glu Val Leu Phe Gln Gly Pro
1 5
<210> 10
<211> 4575
<212> DNA
<213> Artificial Sequence
<400> 10
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaatcggat 660
ctggaagttc tgttccaggg gcccctggga tccatgcctt tcgttaacaa acagtttaac 720
tataaggacc cggttaacgg tgtggatatt gcatacatta agatccctaa cgctggtcag 780
atgcagccgg tgaaagcatt caagatccac aataagattt gggtgatccc ggaacgcgat 840
acctttacca acccggaaga aggcgatctg aacccccctc cggaggccaa gcaagttccc 900
gttagctatt acgacagtac ctatttaagc accgataatg agaaagataa ctatctgaag 960
ggtgttacca aactgttcga gcgcatctac agcacagact taggccgcat gctgctgacc 1020
agtatcgttc gtggtattcc gttctggggc ggcagtacca tcgacaccga gctgaaagtg 1080
atcgacacca attgcattaa cgtgatccag cccgatggca gctatcgtag cgaagagctg 1140
aatctggtta tcatcggccc tagtgccgac attattcaat tcgagtgtaa aagcttcggc 1200
catgaggtgc tgaatttaac ccgtaatggc tatggcagta cccagtacat ccgcttcagc 1260
ccggatttta ccttcggctt cgaggaatct ttagaagtgg ataccaatcc gctgctgggc 1320
gccggcaaat ttgcaacaga ccccgctgtt actttagccc atgagctgat tcatgctggt 1380
catcgtctgt acggcatcgc cattaacccg aaccgtgtgt ttaaggttaa caccaacgcc 1440
tattatgaaa tgagtggttt agaggtgagc ttcgaggagc tgcgtacctt tggtggccat 1500
gatgccaagt tcatcgatag tctgcaagaa aacgagtttc gtctgtatta ttacaacaag 1560
ttcaaagata tcgcaagcac cttaaataaa gccaagagca tcgttggcac caccgcctct 1620
ttacaatata tgaaaaacgt tttcaaggag aaatatctgc tgagcgagga caccagtggt 1680
aaatttagtg ttgacaaact gaagttcgat aaactgtata agatgctgac cgagatctat 1740
accgaagaca atttcgtgaa attttttaaa gttctgaatc gcaaaacata tttaaacttc 1800
gacaaagcag tgtttaaaat caacatcgtt ccgaaggtta attacacaat ctacgatggc 1860
ttcaatttac gcaacaccaa tttagccgca aacttcaacg gccaaaatac cgagatcaat 1920
aacatgaatt tcaccaaact gaaaaacttt actggtttat ttgagttcta caaactgctg 1980
tgcgtgcgtg gcattatcac cagtttagaa gtgctgtttc aaggtccggc cttaaacgat 2040
ctgtgtatta aagttaacaa ttgggatctg tttttcagcc ctagcgagga caattttacc 2100
aacgatttaa acaaaggcga ggagatcacc agcgatacca atattgaggc cgcagaggag 2160
aatatcagtc tggatttaat ccagcaatat tatctgacct ttaattttga caatgagccg 2220
gagaacatta gtatcgaaaa tttaagtagc gacatcattg gtcagctgga gctgatgccg 2280
aacattgagc gcttcccgaa tggcaaaaag tatgaattag ataagtacac catgtttcac 2340
tatttacgcg cccaagaatt tgaacacggt aaaagccgta ttgccttaac caacagcgtg 2400
aatgaagcac tgctgaaccc gagccgcgtg tatacctttt tcagtagtga ctatgttaag 2460
aaggtgaata aggccaccga agccgccatg ttcttaggct gggtggagca gctggtgtat 2520
gatttcaccg atgagaccag cgaggtgagc accacagata aaatcgcaga tattacaatt 2580
attattccgt acatcggccc ggctttaaat atcggtaaca tgctgtacaa agatgatttc 2640
gtgggcgctt taatctttag cggtgccgtt attctgttag aattcattcc cgaaattgca 2700
atcccggtgc tgggcacctt tgctttagtt agctatatcg caaataaagt gttaaccgtt 2760
cagaccattg acaatgcttt aagcaagcgt aatgaaaagt gggatgaggt ttataaatac 2820
atcgttacaa attggttagc caaagtgaac acccagattg atttaatccg taagaaaatg 2880
aaagaagcct tagagaatca agctgaggcc acaaaagcaa ttatcaatta ccagtacaat 2940
cagtataccg aagaagaaaa gaacaatatc aactttaata ttgatgattt aagcagcaag 3000
ctgaacgaaa gcattaataa agccatgatt aatattaaca agtttttaaa ccagtgcagc 3060
gtgagctatt taatgaacag catgatccct tacggtgtga agcgtctgga agatttcgat 3120
gcctctttaa aagacgcact gttaaagtat atttatgaca atcgcggcac actgatcggt 3180
caagttgatc gtctgaaaga taaagttaat aacacattaa gcacagacat tcctttccag 3240
ctgagtaaat acgtggacaa tcaacgtctg ctgagcacct ttaccgaata cattaaaaac 3300
attattaaca ccagcattct gaatttacgc tacgagagca accatttaat tgatctgagc 3360
cgttacgcca gcaagatcaa tatcggtagc aaggttaact tcgacccgat tgacaaaaac 3420
cagatccagt tattcaattt agagagtagt aagattgagg ttattttaaa aaacgccatc 3480
gtttataaca gcatgtacga aaattttagc acaagctttt ggattcgtat cccgaagtat 3540
ttcaatagca tctctttaaa taatgaatac acaatcatta attgcatgga aaacaacagc 3600
ggctggaagg tgtctttaaa ctacggtgag atcatctgga ctttacaaga tacccaagaa 3660
atcaagcagc gcgttgtgtt caaatatagt cagatgatca acattagtga ctatattaac 3720
cgctggattt ttgtgaccat cacaaataac cgtttaaaca acagcaaaat ttatattaac 3780
ggtcgtctga ttgaccagaa gccgattagc aatttaggta atatccatgc cagcaacaac 3840
attatgttca aactggatgg ttgtcgcgat acccatcgct acatctggat taagtacttt 3900
aacttattcg acaaagaact gaatgaaaag gagatcaagg acttatatga taatcaaagc 3960
aatagcggca ttttaaaaga cttttggggt gactatctgc agtatgacaa accttactat 4020
atgctgaact tatatgaccc gaacaaatac gttgacgtga acaatgtggg tattcgtggc 4080
tacatgtatc tgaaaggccc gcgcggcagt gttatgacca caaatattta tttaaacagc 4140
tctttatatc gtggcaccaa gtttatcatc aagaagtacg caagcggcaa taaagacaat 4200
attgtgcgta acaacgatcg tgtgtacatc aacgttgtgg tgaagaacaa agagtatcgt 4260
ttagccacca atgccagcca agctggtgtg gaaaaaattt taagcgcact ggagatcccc 4320
gatgtgggca atttaagtca agttgttgtg atgaaaagta agaatgatca aggcatcacc 4380
aacaaatgta agatgaattt acaagacaat aacggcaatg acattggttt tattggtttc 4440
catcagttca acaatatcgc aaagctggtg gccagcaact ggtacaaccg tcagatcgaa 4500
cgtagcagcc gtactttagg ttgcagctgg gaatttattc cggtggatga tggttggggt 4560
gagcgccctt tataa 4575
<210> 11
<211> 1524
<212> PRT
<213> Artificial Sequence
<400> 11
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu
210 215 220
Phe Gln Gly Pro Leu Gly Ser Met Pro Phe Val Asn Lys Gln Phe Asn
225 230 235 240
Tyr Lys Asp Pro Val Asn Gly Val Asp Ile Ala Tyr Ile Lys Ile Pro
245 250 255
Asn Ala Gly Gln Met Gln Pro Val Lys Ala Phe Lys Ile His Asn Lys
260 265 270
Ile Trp Val Ile Pro Glu Arg Asp Thr Phe Thr Asn Pro Glu Glu Gly
275 280 285
Asp Leu Asn Pro Pro Pro Glu Ala Lys Gln Val Pro Val Ser Tyr Tyr
290 295 300
Asp Ser Thr Tyr Leu Ser Thr Asp Asn Glu Lys Asp Asn Tyr Leu Lys
305 310 315 320
Gly Val Thr Lys Leu Phe Glu Arg Ile Tyr Ser Thr Asp Leu Gly Arg
325 330 335
Met Leu Leu Thr Ser Ile Val Arg Gly Ile Pro Phe Trp Gly Gly Ser
340 345 350
Thr Ile Asp Thr Glu Leu Lys Val Ile Asp Thr Asn Cys Ile Asn Val
355 360 365
Ile Gln Pro Asp Gly Ser Tyr Arg Ser Glu Glu Leu Asn Leu Val Ile
370 375 380
Ile Gly Pro Ser Ala Asp Ile Ile Gln Phe Glu Cys Lys Ser Phe Gly
385 390 395 400
His Glu Val Leu Asn Leu Thr Arg Asn Gly Tyr Gly Ser Thr Gln Tyr
405 410 415
Ile Arg Phe Ser Pro Asp Phe Thr Phe Gly Phe Glu Glu Ser Leu Glu
420 425 430
Val Asp Thr Asn Pro Leu Leu Gly Ala Gly Lys Phe Ala Thr Asp Pro
435 440 445
Ala Val Thr Leu Ala His Glu Leu Ile His Ala Gly His Arg Leu Tyr
450 455 460
Gly Ile Ala Ile Asn Pro Asn Arg Val Phe Lys Val Asn Thr Asn Ala
465 470 475 480
Tyr Tyr Glu Met Ser Gly Leu Glu Val Ser Phe Glu Glu Leu Arg Thr
485 490 495
Phe Gly Gly His Asp Ala Lys Phe Ile Asp Ser Leu Gln Glu Asn Glu
500 505 510
Phe Arg Leu Tyr Tyr Tyr Asn Lys Phe Lys Asp Ile Ala Ser Thr Leu
515 520 525
Asn Lys Ala Lys Ser Ile Val Gly Thr Thr Ala Ser Leu Gln Tyr Met
530 535 540
Lys Asn Val Phe Lys Glu Lys Tyr Leu Leu Ser Glu Asp Thr Ser Gly
545 550 555 560
Lys Phe Ser Val Asp Lys Leu Lys Phe Asp Lys Leu Tyr Lys Met Leu
565 570 575
Thr Glu Ile Tyr Thr Glu Asp Asn Phe Val Lys Phe Phe Lys Val Leu
580 585 590
Asn Arg Lys Thr Tyr Leu Asn Phe Asp Lys Ala Val Phe Lys Ile Asn
595 600 605
Ile Val Pro Lys Val Asn Tyr Thr Ile Tyr Asp Gly Phe Asn Leu Arg
610 615 620
Asn Thr Asn Leu Ala Ala Asn Phe Asn Gly Gln Asn Thr Glu Ile Asn
625 630 635 640
Asn Met Asn Phe Thr Lys Leu Lys Asn Phe Thr Gly Leu Phe Glu Phe
645 650 655
Tyr Lys Leu Leu Cys Val Arg Gly Ile Ile Thr Ser Leu Glu Val Leu
660 665 670
Phe Gln Gly Pro Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp
675 680 685
Asp Leu Phe Phe Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn
690 695 700
Lys Gly Glu Glu Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu
705 710 715 720
Asn Ile Ser Leu Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe
725 730 735
Asp Asn Glu Pro Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile
740 745 750
Ile Gly Gln Leu Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly
755 760 765
Lys Lys Tyr Glu Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala
770 775 780
Gln Glu Phe Glu His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val
785 790 795 800
Asn Glu Ala Leu Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser
805 810 815
Asp Tyr Val Lys Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu
820 825 830
Gly Trp Val Glu Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu
835 840 845
Val Ser Thr Thr Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr
850 855 860
Ile Gly Pro Ala Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe
865 870 875 880
Val Gly Ala Leu Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile
885 890 895
Pro Glu Ile Ala Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr
900 905 910
Ile Ala Asn Lys Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser
915 920 925
Lys Arg Asn Glu Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn
930 935 940
Trp Leu Ala Lys Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met
945 950 955 960
Lys Glu Ala Leu Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn
965 970 975
Tyr Gln Tyr Asn Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe
980 985 990
Asn Ile Asp Asp Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala
995 1000 1005
Met Ile Asn Ile Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu
1010 1015 1020
Met Asn Ser Met Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp
1025 1030 1035 1040
Ala Ser Leu Lys Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly
1045 1050 1055
Thr Leu Ile Gly Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr
1060 1065 1070
Leu Ser Thr Asp Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln
1075 1080 1085
Arg Leu Leu Ser Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr
1090 1095 1100
Ser Ile Leu Asn Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu Ser
1105 1110 1115 1120
Arg Tyr Ala Ser Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp Pro
1125 1130 1135
Ile Asp Lys Asn Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile
1140 1145 1150
Glu Val Ile Leu Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn
1155 1160 1165
Phe Ser Thr Ser Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile
1170 1175 1180
Ser Leu Asn Asn Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser
1185 1190 1195 1200
Gly Trp Lys Val Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln
1205 1210 1215
Asp Thr Gln Glu Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met
1220 1225 1230
Ile Asn Ile Ser Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr
1235 1240 1245
Asn Asn Arg Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile
1250 1255 1260
Asp Gln Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn
1265 1270 1275 1280
Ile Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp
1285 1290 1295
Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu Ile
1300 1305 1310
Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys Asp Phe
1315 1320 1325
Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met Leu Asn Leu
1330 1335 1340
Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val Gly Ile Arg Gly
1345 1350 1355 1360
Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val Met Thr Thr Asn Ile
1365 1370 1375
Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr Lys Phe Ile Ile Lys Lys
1380 1385 1390
Tyr Ala Ser Gly Asn Lys Asp Asn Ile Val Arg Asn Asn Asp Arg Val
1395 1400 1405
Tyr Ile Asn Val Val Val Lys Asn Lys Glu Tyr Arg Leu Ala Thr Asn
1410 1415 1420
Ala Ser Gln Ala Gly Val Glu Lys Ile Leu Ser Ala Leu Glu Ile Pro
1425 1430 1435 1440
Asp Val Gly Asn Leu Ser Gln Val Val Val Met Lys Ser Lys Asn Asp
1445 1450 1455
Gln Gly Ile Thr Asn Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly
1460 1465 1470
Asn Asp Ile Gly Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys
1475 1480 1485
Leu Val Ala Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg
1490 1495 1500
Thr Leu Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly
1505 1510 1515 1520
Glu Arg Pro Leu
Claims (17)
1.一种肉毒毒素蛋白组合物,其特征在于,包括以下组分:
肉毒毒素蛋白和蛋白稳定剂;
所述蛋白稳定剂选自氨基酸或类氨基酸化合物中任一种。
2.如权利要求1所述的组合物,其特征在于,所述类氨基酸化合物包括左旋卡尼汀(L-carnitine)。
3.如权利要求2所述的组合物,其特征在于,所述左旋卡尼汀的摩尔含量为5-20mM。
4.如权利要求1所述的组合物,其特征在于,所述氨基酸的摩尔含量为5-20mM。
5.如权利要求4所述的组合物,其特征在于,所述氨基酸选自L-组氨酸、L-甘氨酸、L-精氨酸、L-甲硫氨酸、L-组氨酸和L-赖氨酸中的一种或多种。
6.如权利要求1-5任一项所述的组合物,其特征在于,所述肉毒毒素蛋白选自A型肉毒毒素蛋白、B型肉毒毒素蛋白、C1型肉毒毒素蛋白、C2型肉毒毒素蛋白、D型肉毒毒素蛋白、E型肉毒毒素蛋白、F型肉毒毒素蛋白、G型肉毒毒素蛋白或H型肉毒毒素蛋白中的任一种;优选的,所述肉毒毒素蛋白为A型肉毒毒素蛋白,更优选的,所述肉毒毒素为重组肉毒毒素。
7.如权利要求1-6任一项所述的组合物,其特征在于,所述组合物还包括增溶剂和/或盐类。
8.如权利要求7所述的组合物,其特征在于,所述增溶剂的体积百分比浓度为0.01%-0.2%。
9.如权利要求7-8任一项所述的组合物,其特征在于,所述的盐类的质量百分比为0.9%。
10.如权利要求7-9任一项所述的组合物,其特征在于,所述增溶剂选自吐温类、司盘类、十二烷基硫酸钠;
优选的,所述吐温类选自吐温20、吐温40、吐温60、或吐温80中的一种或多种;
优选的,所述司盘类选自司盘20、司盘40、司盘60、司盘80、或司盘85中的一种或多种;
更优选的,所述增溶剂为吐温80。
11.如权利要求7-10任一项所述的组合物,其特征在于,所述盐类选自无机盐或有机盐中任一种;
优选的,所述无机盐选自氯化钠、磷酸钠、硫酸镁、乙酸钠、丙酸钠和磷酸钾中的一种或多种;
优选的,所述有机盐选自乳酸钠、琥珀酸钠中的一种或多种;
更优选的,所述无机盐类为氯化钠。
12.如权利要求1-11任一项所述的组合物,其特征在于,所述组合物包括肉毒毒素蛋白、左旋卡尼汀、吐温80、氯化钠;
或,
所述组合物包括肉毒毒素蛋白、氨基酸、吐温80、氯化钠。
13.如权利要求12所述的组合物,其特征在于,所述吐温80的体积百分比浓度为0.05%-0.2%;
优选的,所述吐温80的体积百分比浓度为0.1%。
14.如权利要求12-13任一项所述的组合物,其特征在于,所述氯化钠的质量百分比浓度为0.9%。
15.如权利要求1-14任一项所述的组合物,其特征在于,所述组合物为液体制剂。
16.一种权利要求1-15任一项所述的组合物的制备方法,其特征在于,所述制备方法包括将各组分混合的步骤。
17.权利要求1-15任一项所述的组合物在制备用于预防和/或治疗支配肌肉或外分泌腺的胆碱能神经相关疾病的药物中的应用,
或,
在制备用于医学美容中药物的应用;
优选的,所述医学美容包括平滑或预防皱纹、瘦脸、形体塑型、疤痕修复;
优选的,所述的胆碱能神经相关疾病选自:
弗雷综合征、鳄鱼泪综合征、腋下多汗症、足底多汗症、头颈多汗症、身体多汗症、鼻漏、帕金森氏病、肌萎缩侧索硬化、多涎、垂涎、流涎、痉挛状况、腭肌阵挛、肌阵挛、肌纤维颤搐、僵直、良性肌肉痉挛、遗传性下巴颤抖、反常性下颌肌肉活动、半侧咀嚼肌痉挛、肥大型鳃肌病、嚼肌肥大、胫骨前肌肥大、眼球震颤、振动幻视、核上凝视麻痹、持续状态部分性癫痫、痉挛性斜颈手术计划、展肌声带麻痹、顽固性突变性发音障碍、上食道括约肌功能障碍、声带肉芽肿、口吃、抽动秽语综合征、中耳肌阵挛、保护性喉闭合、喉切除术后言语失败、保护性上睑下垂、睑内翻、奥狄氏括约肌功能障碍、假性食道弛缓不能、非失弛缓性食道运动障碍、阴道痉挛、术后卧床、震颤、膀胱功能障碍、半面痉挛、神经支配恢复术运动障碍、僵人综合征、破伤风、前列腺增生、肥胖治疗、婴儿大脑性麻痹、失弛缓症和肛裂中的一种或多种。
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