CN109310641A - 用于受控和持续释放的elp融合蛋白 - Google Patents
用于受控和持续释放的elp融合蛋白 Download PDFInfo
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Abstract
本发明提供了用于持续释放的药物制剂,和用具有持续释放和较长半衰期组合的制剂的递送治疗方案的方法。本发明提供了肽和小分子药物的改进的药代动力学。
Description
相关申请的交叉引用
本发明要求2017年1月4日提交的美国临时申请号62/442,057和2016年5月6日提交的美国临时申请号62/332,803的优先权,其各自的内容以其整体通过引用合并于此。
发明领域
本发明涉及用于持续释放的药物制剂,和用该持续释放制剂递送治疗方案的方法。
电子提交的文本发明件说明
以电子方式提交的文本发明件的内容通过引用整体并入本发明:序列表的计算机可读格式副本(文件名:PHAS_033_02WO_SeqList_ST25.txt,记录日期:2017年5月1日,文件大小287千字节)。
背景技术
肽和小分子药物的有效性通常受到此类药物在循环中的半衰期以及难以获得基本上恒定的血浆水平的限制。例如,肠促胰岛素GLP-1必须以相对较高的剂量施用以克服其在循环中较短的半衰期,此外,这些较高的剂量与恶心相关(Murphy和Bloom,Nonpeptidic glucagon-like peptide 1 receptor agonists:A magic bullet for diabetes?PNAS104(3):689-690(2007))。而且,在一些评估中,肽药剂血管活性肠肽(vasoactive intestinalpeptide,VIP)显示出低于1分钟的半衰期,这使得该药剂无法作为药物使用(Domschke等,Vasoactive intestinal peptide in man:pharmacokinetics,metabolic and circulatory effects,Gut 19:1049-1053(1978);Henning和Sawmiller,Vasoactive intestinal peptide:cardiovascular effects,Cardiovascular Research 49:27-37(2001))。肽类药物较短的血浆半衰期通常是由于其在体循环中具有迅速的肾脏清除率和酶促降解所致。
发明内容
本发明提供用于持续释放的药物制剂以及用持续释放制剂递送治疗方案的方法。本发明因此提供肽和小分子药物的改善药代动力学。
在一些方面,本发明提供持续释放药物制剂。该制剂包含供全身性施用的治疗剂,其中该治疗剂包含活性剂和能够在受试者体温下形成可逆基质的氨基酸序列。该可逆基质由氢键(例如,分子内和/或分子间氢键)以及疏水性贡献而形成。该制剂还包含一种或多种药学上可接受的赋形剂和/或稀释剂。该基质允许从注射部位缓慢吸收进循环。从注射部位的持续释放或缓慢吸收归因于在注射部位浓度消散时基质的缓慢逆转。一旦产物进入循环后,制剂即赋予长半衰期和改善的稳定性。因此,实现了缓慢吸收与长半衰期的独特组合,从而导致具有低峰谷比(Cmax比Cmin)和延迟或较晚的Tmax的所需PK曲线。
在一些实施方案中,能在受试者体温形成可逆基质的氨基酸序列是弹性蛋白样肽(ELP)序列。ELP序列包含与弹性蛋白中存在的重复序列相关的结构肽单元或序列(或为该重复序列的模拟物),或由这些结构肽单元或序列组成。ELP氨基酸序列在选定的制剂中可表现出可见和可逆的反向相变。也就是说,氨基酸序列在转变温度(Tt)以下可在结构上无序并高度溶于制剂,但当制剂的温度升到Tt以上时表现出尖锐的(2-3℃范围)无序到有序的相变。在一些实施方案中,本发明提供的治疗剂具有约26℃至约37℃的转变温度。除了温度之外,ELP聚合物的长度、ELP的氨基酸组成、离子强度、pH、压力、所选的溶剂、有机溶质的存在和蛋白浓度也可影响转变性质,并且这些方面可根据所需的吸收特性而定制。在一些实施方案中,蛋白质浓度和盐浓度影响转变性质(例如转变温度)。形成基质的ELP氨基酸序列的其他示例性序列或结构在本发明进行了公开。
在一些实施方案中,供全身性施用的活性剂为蛋白或肽,其可具有诸如约30秒至约1小时、至约2小时或至约5小时的短循环半衰期。在一些实施方案中,蛋白或肽具有约30秒至约10小时的循环半衰期。治疗剂可以是蛋白活性剂与能够形成基质的氨基酸序列之间的重组融合蛋白。示例性肽活性剂包括爱帕琳肽、精氨酸酶、C-型利钠肽(CNP)、GLP-1受体拮抗剂、GLP-2受体激动剂、铁调素、IGF-1、尿扩张素、胸腺素β4、TNF-相关的凋亡-诱导配体(TRAIL)、甲状旁腺激素片段(例如残基1-34)、全长甲状旁腺激素、促肾上腺皮质激素、Coversin、亲吻促动素(kisspeptin)、亲吻促动素片段(例如氨基酸残基1-10或氨基酸残基1-54)、膜联蛋白A1-衍生的肽(例如氨基酸残基2-26)、FGF21,或其衍生物、类似物、模拟物、组合或片段。用于根据本发明递送的小分子药物在本发明进行了公开。通过提供从注射部位的缓慢吸收,可控制肾脏清除率和降解,从而实现所需的PK曲线。
在另一方面,本发明提供递送活性剂的持续释放方案的方法。该方法包括向有需要的受试者施用本发明所述的制剂,其中制剂每个月施用约1次至约8次。在一些实施方案中,制剂约每周施用一次,并可经皮下或肌内(例如)施用。在一些实施方案中,施用部位不是病理部位,也就是说,治疗剂不直接施用到预期作用部位。
附图说明
图1A-B显示CNP构建体的效力。
图2A-C显示了每周三次用PE0552或盐水(对照)皮下注射五周龄雄性FVB/nJ小鼠(n=12/组)对生长的影响。通过测量鼻子到尾巴的长度(A)、鼻子到肛门长度(B)和尾巴的长度(C)来确定对生长的影响。该图显示每组的平均测量值和标准偏差。
图3A-C显示每天用PE9206、PE9216、PE9306、PE9326或盐水(对照)皮下注射三周龄雄性FVB/nJ小鼠(n=11/组)达3周对生长的影响。通过测量鼻子到尾巴的长度(A)、鼻子到肛门的长度(B)和尾巴长度(C)来确定对生长的影响。该图显示了3周时间内生长相对基线的平均变化。
图4显示了雄性Sprague Dawley大鼠(200-220g,n=12/组)在11天给药期间皮下注射PE0503或GLP-2(A2G)对小肠重量的影响。给药如下:每天给予生理盐水的载体组;PE0503Q1D,每天一次以1.3mg/kg的剂量给予PE0503;PE0503Q2D,以5.1mg/kg的剂量每隔一天给予PE0503;PE0503Q4D,以20.5mg/kg的剂量每四天给予一次PE0503;GLP-2(A2G)TID,以0.1mg/kg GLP2(A2G)每天给予两次。
发明详述
本发明提供持续释放的药物制剂以及用持续释放制剂递送治疗方案的方法。在一些实施方案中,本发明公开的药物组合物具有增强的功效、生物利用度、循环半衰期、持久性、降解抗性等。本发明因而提供活性剂如肽和小分子药物的改善药代动力学,包括具有低峰谷比和/或长Tmax的相对平坦的PK曲线。该PK曲线可通过相对不频繁的施用计划而得以维持,诸如在一些实施方案中每个月注射一至八次。
在一些方面,本发明提供持续释放药物制剂。该制剂包含供全身性施用的治疗剂,其中该治疗剂包含活性剂和能够在受试者体温下形成基质或凝聚体(coacervate)的氨基酸序列。该可逆基质由氢键(例如,分子内和/或分子间氢键)以及疏水性贡献而形成。该制剂还包含一种或多种药学上可接受的赋形剂和/或稀释剂。该基质允许从注射部位缓慢吸收进循环。不受理论束缚,这种缓慢的吸收是由于注射部位贮库(depot)周围的基质或凝聚体的缓慢逆转。该缓慢吸收特性允许平坦的PK曲线以及方便而舒适的施用方案。例如,在多种实施方案中,在数天的过程中(例如2至约60天、或约4至约30天)活性剂的血浆浓度的变化系数不超过20、或不超过约10、或不超过约5或不超过约3。一般来讲,该平坦的PK曲线在制剂的多次(大致均匀间隔开的)施用的过程中观察到,诸如至少约2次、至少约5次或至少约10次施用。在一些实施方案中,缓慢吸收通过大于约5小时、大于约10小时、大于约20小时、大于约30小时或大于约50小时的Tmax(达到最高血浆浓度的时间)表现。
形成可逆基质的氨基酸序列
从注射部位的持续释放或缓慢吸收通过能够在受试者体温下形成氢键结合基质或凝聚体的氨基酸序列控制。
在一些实施方案中,氨基酸序列包含通过蛋白骨架基团和/或侧链基团形成氢键并可向基质的形成贡献疏水性相互作用的结构单元。在一些实施方案中,氨基酸侧链不含氢键供体基团,而氢键基本上通过蛋白骨架形成。示例性氨基酸包括脯氨酸、丙氨酸、缬氨酸、甘氨酸和异亮氨酸以及类似的氨基酸。在一些实施方案中,结构单元基本上为重复结构单元,以便形成基本上重复的结构基序和基本上重复的氢键结合能力。在这些和其他实施方案中,氨基酸序列包含可以基本上重复的模式设置的至少约10%、至少约20%、至少约40%或至少约50%的脯氨酸。在此背景下,基本上重复的模式意指氨基酸序列的脯氨酸残基中至少约50%或至少约75%是可限定的结构单元的部分。在另外其他实施方案中,氨基酸序列包含具有氢键供体侧链的氨基酸,诸如丝氨酸、苏氨酸和/或酪氨酸。在一些实施方案中,重复序列可包含一至约四个脯氨酸残基,而其余的残基独立地选自非极性残基,诸如甘氨酸、丙氨酸、亮氨酸、异亮氨酸和缬氨酸。非极性或疏水性残基可向基质的形成贡献疏水性相互作用。
在其他实施方案中,能够在体温下形成所述基质的氨基酸序列可以包含无规卷曲和非球状伸展结构。例如,能够在体温下形成所述基质的氨基酸序列可以包含美国专利公开No.2008/0286808、WIPO专利公开No.2008/155134和美国专利公开No.2011/0123487中公开的氨基酸序列,其均通过引用并入本发明。
在一些实施方案中,氨基酸序列包含至少40个氨基酸的非结构化重组聚合物。非结构化聚合物可包含多于约100、约150、约200或更多个连续氨基酸。在一些实施方案中,氨基酸序列形成无规卷曲结构域。特别地,具有或形成“无规卷曲构象”的多肽或氨基酸聚合物基本上缺乏确定的二级和三级结构。在一些实施方案中,非结构化聚合物定义为具有至少40个氨基酸的聚合物,其中甘氨酸(G)、天冬氨酸(D)、丙氨酸(A)、丝氨酸(S)、苏氨酸(T)、谷氨酸(E)和脯氨酸(P)残基的总量占聚合物中总氨基酸的超过约80%。在一些实施方案中,通过Chou-Fasman算法测定,至少50%的氨基酸缺乏二级结构。
氨基酸序列可在高于储存温度的温度下注射时形成“凝胶样”状态。示例性序列具有重复肽单元,和/或可在较低的温度下相对非结构化并在较高的温度下实现氢键结合的、结构化的状态。
弹性蛋白样肽(ELP)
在一些实施方案中,能够在体温下形成基质的氨基酸序列是具有四至十个氨基酸的重复单元的肽。重复单元可在基质的形成中形成一个、两个或三个氢键。在一些实施方案中,能够在体温下形成基质的氨基酸序列是丝、弹性蛋白、胶原、角蛋白或其模拟物的氨基酸序列,或在据此以引用方式并入的美国专利6,355,776中所公开的氨基酸序列。
在一些实施方案中,氨基酸序列是弹性蛋白样肽(ELP)序列。ELP序列包含与弹性蛋白或其模拟物相关的结构肽单元或序列,或由这些结构肽单元或序列组成。ELP序列由三至约二十个氨基酸、或在一些实施方案中约四至约十个氨基酸(诸如约四个、约五个或约六个氨基酸)的结构单元构成。各个结构单元的长度可以变化或可以一致。示例性结构单元由SEQ ID NO:1-13(以下)定义,这些单元可用作重复结构单元(包括串联重复单元)或可按一定的组合使用。因此,ELP可包含选自如下定义的SEQ ID NO:1-13的结构单元或由其组成。
在一些实施方案(包括其中结构单元为ELP单元的实施方案)中,氨基酸序列包含以下个数的结构单元或基本上由以下个数的结构单元组成:约1至约500个结构单元,或在一些实施方案中约9至约200个结构单元,或在一些实施方案中约10至200个结构单元,或在一些实施方案中约50至约200个结构单元,或在一些实施方案中约80至约200个结构单元,或约80至约150个结构单元。在一些实施方案中,结构单元是由SEQ ID NO:1-13中的一个或多个定义的ELP单元。在一些实施方案中,ELP包括由SEQ ID NO:1-13定义的单元的组合。因此,结构单元一起可具有约50至约2000个氨基酸残基、或约100至约800个氨基酸残基、或约200至约700个氨基酸残基、或约400至约600个氨基酸残基的长度。在示例性实施方案中,所述ELP结构单元的氨基酸序列包含以下或基本上由以下组成:约3个结构单元、约7个结构单元、约9个结构单元、约10个结构单元、约15个结构单元、约20个结构单元、约40个结构单元、约80个结构单元、约90个结构单元、约100个结构单元、约120个结构单元、约140个结构单元,约144个结构单元、约160个结构单元、约180个结构单元、约200个结构单元或约500个结构单元。在示例性实施方案中,所述结构单元共同具有的长度为约45个氨基酸残基、约90个氨基酸残基、约100个氨基酸残基、约200个氨基酸残基、约300个氨基酸残基、约400个氨基酸残基、约500个氨基酸残基、约600个氨基酸残基、约700个氨基酸残基、约720个氨基酸残基、约800个氨基酸残基或约1000个氨基酸残基。
氨基酸序列在选定的制剂中可表现出可见和可逆的反向相变。也就是说,氨基酸序列在转变温度(Tt)以下可在结构上无序并高度溶于制剂,但当制剂的温度升到Tt以上时表现出尖锐的(2-3℃范围)无序到有序的相变或凝聚。除了温度之外,氨基酸聚合物的长度、氨基酸组成、离子强度、pH、压力、所选的溶剂、有机溶质的存在、和蛋白浓度也可影响转变性质,并且这些方面可根据所需的吸收特性而定制。吸收特性可容易地通过测定活性剂随着时间推移的血浆浓度或活性而测试。
在一些实施方案中,ELP组分可由包括但不限于以下的结构单元形成:
(a)四肽Val-Pro-Gly-Gly或VPGG(SEQ ID NO:1);
(b)四肽Ile-Pro-Gly-Gly或IPGG(SEQ ID NO:2);
(c)五肽Val-Pro-Gly-X-Gly(SEQ ID NO:3)或VPGXG,其中X是任何天然或非天然氨基酸残基,除了脯氨酸,并且其中X任选地在聚合物或低聚物重复体之中变化;
(d)五肽Ala-Val-Gly-Val-Pro或AVGVP(SEQ ID NO:4);
(e)五肽Ile-Pro-Gly-X-Gly或IPGXG(SEQ ID NO:5),其中X是任何天然或非天然氨基酸残基,并且其中X任选地在聚合物或低聚物重复体之中变化;
(e)五肽Ile-Pro-Gly-Val-Gly或IPGVG(SEQ ID NO:6);
(f)五肽Leu-Pro-Gly-X-Gly或LPGXG(SEQ ID NO:7),其中X是任何天然或非天然氨基酸残基,并且其中X任选地在聚合物或低聚物重复体之中变化;
(g)五肽Leu-Pro-Gly-Val-Gly或LPGVG(SEQ ID NO:8);
(h)六肽Val-Ala-Pro-Gly-Val-Gly或VAPGVG(SEQ ID NO:9);
(i)八肽Gly-Val-Gly-Val-Pro-Gly-Val-Gly或GVGVPGVG(SEQ ID NO:10);
(j)九肽Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly或VPGFGVGAG(SEQ ID NO:11);
(k)九肽Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly或VPGVGVPGG(SEQ ID NO:12);和
(l)五肽Xaa-Pro-Gly-Val-Gly,或XPGVG(SEQ ID NO:13),其中X为任何天然或非天然氨基酸残基,并且其中X任选地在聚合物或低聚物重复体之中变化。
由SEQ ID NO:1-13定义的此类结构单元可形成结构重复单元,或可组合使用以形成ELP。在一些实施方案中,ELP组分完全(或几乎完全)由选自SEQ ID NO:1-13的结构单元之一或组合(例如2、3、4、5、6、7、8、9或10个)形成。在其他实施方案中,ELP组分中的至少约75%或至少约80%或至少约90%由选自SEQ ID NO:1-13并可作为重复单元而存在的结构单元之一或组合形成。
在一些实施方案中,ELP包含Val-Pro-Gly-X-Gly(SEQ ID NO:3)的重复单元,包括串联重复单元,其中X如上所定义,并且其中Val-Pro-Gly-X-Gly(SEQ ID NO:3)单元相对于整个ELP组分(其可以包含非VPGXG(SEQ ID NO:3)的结构单元)所占的百分比大于ELP的约50%或大于约75%或大于约85%或大于约95%。ELP可包含5至15个SEQ ID NO:3的结构单元(例如约9或约10个结构单元)的基序,其中在基序中客体残基X在至少2个或至少3个单元之中变化。客体残基可独立地选自诸如非极性或疏水性残基,诸如氨基酸V、I、L、A、G和W(并可经选择以便保持所需的反向相转变性质)。在一些实施方案中,所述客体残基选自V、G和A。
在一些实施方案中,ELP包含Xaa-Pro-Gly-Val-Gly(SEQ ID NO:13)的重复单元,包括串联重复单元,其中X如上所定义,并且其中Xaa-Pro-Gly-Val-Gly(SEQ ID NO:13)单元相对于整个ELP组分(其可以包含非XPGVG(SEQ ID NO:13)的结构单元)所占的百分比大于ELP的约50%或大于约75%或大于约85%或大于约95%。ELP可包含5至15个SEQ ID NO:13的结构单元(例如约9或约10个结构单元)的基序,其中在基序中客体残基X在至少2个或至少3个单元之中变化。客体残基可独立地选自诸如非极性或疏水性残基,诸如氨基酸V、I、L、A、G和W(并可经选择以便保持所需的反向相转变性质)。在一些实施方案中,所述客体残基选自V和A。
在一些实施方案中,所述ELP包含SEQ ID NO:1-13任一个的重复单元,包括串联重复单元,单独或其组合。在一些实施方案中,所述ELP包含SEQ ID NO:1-13中任一个的两个或更多个组合的重复体。在一些实施方案中,所述ELP包含SEQ ID NO:3和SEQ ID NO:13的重复体。在一些实施方案中,所述ELP包含SEQ ID NO:3和SEQ ID NO:13的重复体,其中客体残基独立地选自诸如非极性或疏水性残基,诸如氨基酸V、I、L、A、G和W(并可经选择以便保持所需的反向相转变性质)。在一些实施方案中,所述客体残基选自V、G和A。
在一些实施方案中,ELP包括9聚体,包括本发明公开的一种或多种ELP结构单元的9个拷贝。在一些实施方案中,ELP包括9聚体,包括本发明公开的五肽的9个拷贝。在一些实施方案中,ELP包括9聚体,包括以任何组合的SEQ ID NO:3和13。在一些实施方案中,ELP包括在SEQ ID NO:3和13之间交替的序列。可以组合不同数量的9聚体的ELP,以产生具有例如9聚体的18、27、36、45、54、63、72、81、90、99、108、117、126、135、144、153、162、171、或180个拷贝的ELP。
在一些实施方案中,所述ELP包括包含SEQ ID NO:3的9聚体,其中客体残基选自V、G和A。在一些实施方案中,所述ELP包括包含SEQ ID NO:3的9聚体,其中V、G和A的比例为7:2:0(α)。在一些实施方案中,所述ELP包括包含SEQ ID NO:3的9聚体,其中V、G和A的比例为7:0:2(βv1)。在一些实施方案中,所述ELP包括包含SEQ ID NO:3的9聚体,其中V、G和A的比例为6:0:3(βv2)。在一些实施方案中,所述ELP包括包含SEQ ID NO:3的9聚体,其中V、G和A的比例为5:2:2(γ)。在一些实施方案中,所述ELP包括包含SEQ ID NO:13的9聚体,其中所述客体残基选自V、G和A。在一些实施方案中,所述ELP包括包含SEQ ID NO:13的9聚体,其中V、G和A的比例为5:0:4(δ)。示例性9聚体公开于表1。表2示出了几种示例性9聚体的转变温度。
表1示例性9聚体中的客体残基比例。ELP聚合物具有的疏水性在10聚体ELP 1系列(最不疏水)和10聚体ELP 4系列(最疏水)之间。
表2比较示例性9聚体与ELP1系列的转变温度。使用Cary分光光度计测量的浊度的变化是ELP生物聚合物相变的结果。
ELP系列(10mg/ml) | 转变温度 |
1系列(pPB1023) | 37℃ |
α(pPE0253) | 29℃ |
βv1(pPE0254) | 28℃ |
βv2(pPE0311) | 31℃ |
γ(pPE0255) | 29℃ |
δ(pPE0256) | 35℃ |
4系列(pPE0002) | 26℃ |
在一些实施方案中,所述ELP包括表1中列出的9聚体的组合。在一些实施方案中,ELP包含α、βv1、βv2和/或δ9聚体的组合。例如,γELP通过在α9聚体和βv1 9聚体之间交替的16个拷贝而构建,直到构建出144聚体。在一些实施方案中,所述ELP包括α和βv1 9聚体的组合。在一些实施方案中,所述ELP包括α和βv2 9聚体的组合。在一些实施方案中,所述ELP包括α和δ9聚体的组合。在一些实施方案中,所述ELP包括βv1和βv2 9聚体的组合。在一些实施方案中,所述ELP包括βv1和δ9聚体的组合。在一些实施方案中,所述ELP包括βv2和δ9聚体的组合。在一些实施方案中,所述ELP包括α、βv1和βv2 9聚体的组合。在一些实施方案中,所述ELP包括α、βv1和δ9聚体的组合。在一些实施方案中,所述ELP包括α、βv2和δ9聚体的组合。例如,在具体的排列中,ELPβv2可包括以下顺序迭代的结构单元中的以下客体残基:A-V-A-V-V-A-V-A-V。可在ELP中将迭代序列序贯重复约10次、约12次、约15次、约16次、约20次、约25次、约30次、约35次或更多。在一些方面,ELP含有约10到约20个迭代序列。在其它方面,ELP含有约15至20个迭代序列。在一些方面,ELP含有约16个迭代序列。
在一些实施方案中,所述ELP包括包含本发明公开的一个或多个ELP结构单元的10个拷贝的10聚体。在一些实施方案中,所述ELP包括包含本发明公开的五肽的10个拷贝的10聚体。在一些实施方案中,所述ELP包括包含任意组合的SEQ ID NO:3和13的10聚体。在一些实施方案中,所述ELP包括在SEQ ID NO:3和13之间交替的序列。具有不同数量10聚体的ELP可组合以产生具有例如10聚体的20、30、40、60、90、100、120、150、160、或200个拷贝的ELP。示例性10聚体公开于表3。
表3示例性10聚体中的客体残基比例。ELP聚合物具有在ELP 1系列(最不疏水)和ELP 4系列(最疏水)之间的疏水性。
在一些实施方案中,ELP可形成β-转角结构。适于形成β-转角结构的示例性肽序列在据此整体以引用方式并入的国际专利申请PCT/US96/05186中有所描述。例如,VPGXG(SEQID NO:3)序列中的第四个残基(X)可发生改变而不会取消β-转角的形成。
可以使用标记ELPk[XiYj-n]描述示例性ELP的结构,其中k表示特定的ELP重复单元,括号内的大写字母是单字母氨基酸代码,其相应的下标表示各客体残基X在结构单元中(在适用的情况下)的相对比例,以及n以结构重复数描述ELP的总长。例如,ELP1[V5A2G3-10]表示含有10个五肽VPGXG(SEQ ID NO:3)重复单元的ELP成分,其中X是相对比例为约5:2:3的缬氨酸、丙氨酸和甘氨酸;ELP1[K1V2F1-4]表示含有4个五肽VPGXG(SEQ ID NO:3)重复单元的ELP成分,其中X是相对比例为约1:2:1的赖氨酸、缬氨酸和苯丙氨酸;ELP1[K1V7F1-9]表示含有9个五肽VPGXG(SEQ ID NO:3)重复单元的多肽,其中X是相对比例为约1:7:1的赖氨酸、缬氨酸和苯丙氨酸;ELP1[V-5]表示含有5个五肽VPGXG(SEQ ID NO:3)重复单元的多肽,其中X是缬氨酸;ELP1[V-20]表示含有20个五肽VPGXG(SEQ ID NO:3)重复单元的多肽,其中X是缬氨酸;ELP2[5]表示含有5个五肽AVGVP(SEQ ID NO:4)重复单元的多肽;ELP3[V-5]表示含有5个五肽IPGXG(SEQ ID NO:5)重复单元的多肽,其中X是缬氨酸;ELP4[V-5]表示含有5个五肽LPGXG(SEQ ID NO:7)重复单元的多肽,其中X是缬氨酸。
关于ELP,Tt是客体残基疏水性的函数。因此,通过改变客体残基的身份及其摩尔分数,可以合成出在较宽温度范围内显示出反相转变的ELP。因此,可以通过在ELP序列中引入更高分数的疏水性客体残基在给定ELP长度下降低Tt。适宜的疏水性客体残基的示例包括缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、色氨酸和甲硫氨酸。也可以使用具有中度疏水性的酪氨酸。相反地,可以通过引入残基增加Tt,如选自下述的那些:谷氨酸、半胱氨酸、赖氨酸、天冬氨酸、丙氨酸、天冬酰胺、丝氨酸、苏氨酸、甘氨酸、精氨酸和谷氨酰胺。
对于分子量>100,000的多肽而言,在PCT/US96/05186中(其通过全文引用并入本发明)公开的疏水性指数提供了用于预测特定ELP序列大致Tt的一种方法。对于分子量<100,000的多肽而言,可以通过下述二次函数预测或确定Tt:Tt=M0+M1X+M2X2,其中X是融合蛋白的MV,和M0=116.21;M1=-1.7499;M2=0.010349。
在一些实施方案中对ELP进行选择或设计以使得Tt的范围为约10至约37℃,如约20至约37℃,或者约25℃至约37℃。在一些实施方案中,考虑到外周体温略有降低,在生理条件下(例如0.9%生理盐水)的转变温度为约34至36℃。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数。在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,且各个X选自V、G和A。在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,各个X选自V、G和A,且其中V:G:A的比例可为约5:3:2。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:3:2。在一些实施方案中,所述ELP包括[VPGXG]90,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:3:2。例如,能在体温形成氢键结合基质的氨基酸序列包括[VPGXG]120,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:3:2。如本发明所示,该ELP的120个结构单元可以约5至15mg/ml(例如,约10mg/ml)的蛋白质提供约37℃的转变温度。在约50至约100mg/mL的浓度,相转变温度为约35.5℃(刚低于体温),这允许外周体温刚好小于37℃。在一些实施方案中,ELP可包括[VPGXG]144,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:3:2。在一些实施方案中,所述ELP包括[VPGXG]180,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:3:2。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。在一些实施方案中,所述ELP包括[VPGXG]90,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。在一些实施方案中,所述ELP包括[VPGXG]108,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。在一些实施方案中,所述ELP包括[VPGXG]120,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。在一些实施方案中,所述ELP包括[VPGXG]144,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。在一些实施方案中,所述ELP包括[VPGXG]180,其中各个X选自V、G和A,且其中V:G:A的比例为约7:2:0。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。在一些实施方案中,所述ELP包括[VPGXG]90,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。在一些实施方案中,所述ELP包括[VPGXG]108,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。在一些实施方案中,所述ELP包括[VPGXG]120,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。在一些实施方案中,所述ELP包括[VPGXG]144,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。在一些实施方案中,所述ELP包括[VPGXG]180,其中各个X选自V、G和A,且其中V:G:A的比例为约7:0:2。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。在一些实施方案中,所述ELP包括[VPGXG]90,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。在一些实施方案中,所述ELP包括[VPGXG]108,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。在一些实施方案中,所述ELP包括[VPGXG]120,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。在一些实施方案中,所述ELP包括[VPGXG]144,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。在一些实施方案中,所述ELP包括[VPGXG]180,其中各个X选自V、G和A,且其中V:G:A的比例为约6:0:3。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。在一些实施方案中,所述ELP包括[VPGXG]90,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。在一些实施方案中,所述ELP包括[VPGXG]108,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。在一些实施方案中,所述ELP包括[VPGXG]120,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。在一些实施方案中,所述ELP包括[VPGXG]144,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。在一些实施方案中,所述ELP包括[VPGXG]180,其中各个X选自V、G和A,且其中V:G:A的比例为约5:2:2。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至200的任何数,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。在一些实施方案中,所述ELP包括[VPGXG]90,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。在一些实施方案中,所述ELP包括[VPGXG]108,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。在一些实施方案中,所述ELP包括[VPGXG]120,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。在一些实施方案中,所述ELP包括[VPGXG]144,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。在一些实施方案中,所述ELP包括[VPGXG]180,其中各个X选自V、G和A,且其中V:G:A的比例为约10:0:0。
在一些实施方案中,所述ELP包括[VPGXG]m,其中m为1至100的任何数,其中各个X选自V和L,且其中V:L的比例为约3:7或约4:6或约1:1或约6:4或约3:7。在一些实施方案中,所述ELP包括[VPGXG]60,其中各个X选自V和L,且其中V:L的比例为约3:7或约4:6或约1:1或约6:4或约3:7。在一些实施方案中,所述ELP包括[VPGXG]50,其中各个X选自V和L,且其中V:L的比例为约3:7或约4:6或约1:1或约6:4或约3:7。在一些实施方案中,所述ELP包括[VPGXG]40,其中各个X选自V和L,且其中V:L的比例为约3:7或约4:6或约1:1或约6:4或约3:7。在一些实施方案中,所述ELP包括[VPGXG]30,其中各个X选自V和L,且其中V:L的比例为约3:7或约4:6或约1:1或约6:4或约3:7在一些实施方案中,所述ELP包括[VPGXG]20,其中各个X选自V和L,且其中V:L的比例为约3:7或约4:6或约1:1或约6:4或约3:7。
在一些实施方案中,所述ELP包括[XPGVG]m,其中m为1至200的任何数。在一些实施方案中,所述ELP包括[XPGVG]m,其中m为1至200的任何数,且各个X选自V、G和A。在一些实施方案中,所述ELP包括[XPGVG]m,其中m为1至200的任何数,各个X选自V、G和A且其中V:G:A的比例为约5:0:4。在一些实施方案中,所述ELP包括[XPGVG]60,其中各个X选自V、G和A,且其中V:G:A的比例为约5:0:4。在一些实施方案中,所述ELP包括[XPGVG]90,其中各个X选自V、G和A,且其中V:G:A的比例为约5:0:4。在一些实施方案中,所述ELP包括[XPGVG]120,其中各个X选自V、G和A,且其中V:G:A的比例为约5:0:4。在一些实施方案中,所述ELP包括[XPGVG]144,其中各个X选自V、G和A,且其中V:G:A的比例为约5:0:4。在一些实施方案中,所述ELP包括[XPGVG]180,其中各个X选自V、G和A,且其中V:G:A的比例为约5:0:4。
在一些实施方案中,所述ELP包括[VPGVG]m其中m为1至200的任何数。在一些实施方案中,所述ELP包括[VPGVG]60,[VPGVG]90,或[VPGVG]120。如本发明所示,该ELP的120个结构单元可以约0.005至约0.05mg/ml(例如,约0.01mg/ml)的蛋白质提供约37℃的转变温度。或者,所述ELP包括[VPGXG]144或[XPGVG]144。如本发明所示(表2),这些144个结构单元的ELP中任一个可提供28℃至35℃(包括端点)的转变温度。
在不同实施方式中,目标受试者是人,并且体温是约37℃,并且因此将所述治疗剂设计为在此温度或接近此温度下(例如约28℃至约37℃)提供持续释放。缓慢释放进入循环以及氢键和/或疏水性相互作用的逆转由在注射部位产物扩散的浓度下降所驱动,尽管体温仍保持恒定。在其他实施方案中,所述受试者是非人哺乳动物,并且将所述治疗剂设计为在所述哺乳动物的体温下显示出持续释放,其在一些实施方案中可以是约30至约40℃,如针对一些家养宠物(例如狗或猫)或家畜(例如牛、马、绵羊或猪)。在通常情况下,Tt高于制剂的贮存条件(其可以是2至约25℃,或者15至22℃),这样所述治疗剂仍是注射用溶液。
在一些实施方案中,所述ELP可提供的转变温度范围为27℃至36℃,包括端点。在一些实施方案中,所述ELP可提供的转变温度范围为28℃至35℃,包括端点。在一些实施方案中,所述ELP可提供的转变温度范围为29℃至34℃,包括端点。在一些实施方案中,所述ELP可提供的转变温度范围为27℃至33℃,包括端点。在一些实施方案中,所述ELP可提供的转变温度范围为30℃至33℃,包括端点。在一些实施方案中,所述ELP可提供的转变温度范围为31℃至31℃,包括端点。在一些实施方案中,所述ELP可提供的转变温度为27℃、28℃、29℃、30℃、31℃、32℃、33℃、34℃、35℃、或36℃。在一些实施方案中,所述ELP在蛋白质浓度为10mg/mL时在110mM NaCl中可提供的转变温度范围为28℃至35℃,包括端点。
弹性蛋白样肽(ELP)蛋白质聚合物和重组融合蛋白可如美国专利公开号2010/0022455中所述制备,其通过引用并入本发明。在一些实施方案中,通过递归连接(recursive ligation)构建ELP蛋白聚合物,以快速克隆编码大范围的分子量的任何序列和规定长度的高度重复多肽的DNA。在单个循环中,将各含有寡聚体拷贝的亲本质粒的两个半部连接在一起,从而使寡聚体二聚化并且重建功能性质粒。递归实施该过程以装配具有期望数目的重复的寡聚基因。例如,将一个ELP结构亚基(例如五肽或五肽的9聚体)插入载体中。消化载体,并且插入另一种ELP结构单元(例如五肽或五肽的9聚体)。每个随后的消化和连接轮次使包含在所得载体中的ELP结构单元的数目倍增,直到ELP聚合物为期望的长度。通过改变初始结构单元中的五肽数目,可容易地构建不同长度的ELP。可使用备选的构造手段(即除了递归连接之外)来产生ELP的备选长度。
在一些实施方案中,载体含有一个或多个另外的氨基酸或ELP结构单元重复。例如,pPE0248在客体位置中具有缬氨酸的情况下对144聚体的N端添加另外的五聚体重复,并且在客体残基位中具有色氨酸的情况下对C端添加另外的五聚体。色氨酸可用作增加分子消光系数的手段,这允许更好地测量吸光度,例如在280nm(其可用于测定蛋白质浓度),或用于在纯化过程中监测蛋白质含量。也可设计对任一端添加的五聚体,使得编码DNA含有限制性酶识别位点,用于将融合配偶体克隆到ELP编码序列的任一端上。
在一些实施方案中,治疗剂包含活性剂和一种或多种ELP。在一些实施方案中,治疗剂包括在N-或C端具有一个或多个ELP的活性剂。在一些实施方案中,治疗剂包括在N-或C端两者具有一个或多个ELP的活性剂。在一些实施方案中,ELP是大致相同的大小。在一些实施方案中,ELP在大小上不同。在一些实施方案中,一个末端的ELP大于另一个末端的ELP。在一些实施方案中,N端的ELP大于C端的ELP。在一些实施方案中,C端的ELP大于N端的ELP。
活性剂
蛋白活性剂
在不同实施方案中,活性剂为蛋白或肽,其本身可具有诸如约30秒至约1小时的短循环半衰期。治疗剂可以是蛋白活性剂与能够在受试者体温下形成氢键结合基质的氨基酸序列(例如ELP)之间的重组融合蛋白。任何合适的蛋白活性剂可用于本发明的治疗剂。在不同实施方案中,所述蛋白活性剂为激活素受体2A细胞外结构域、促肾上腺皮质激素(ACTH)、α-2巨球蛋白、α-MSH/阿法诺肽(afamelanotide)、胰淀素(普兰林肽)、血管紧张素(1-7)、膜联蛋白A1、爱帕琳肽、精氨酸酶、门冬酰胺酶、缓激肽B2受体拮抗剂、坎普他汀(Compstatin)、Coversin、CTLA-4、C-型利钠肽、cenderitide(CD-NP)、Elafin、毒晰外泌肽(exendin)-4、成纤维细胞生长因子(FGF)-18/sprifermin、FGF-19、FGF-21、甘丙肽、粒细胞集落刺激因子(G-CSF)、饥饿素、GLP-1/GIP双重激动剂、GLP-1/胰高血糖素双重激动剂、GLP-1/GLP-2双重激动剂、胰高血糖素、胰高血糖素样肽(GLP)-1受体拮抗剂、GLP-2、粒细胞巨噬细胞集落刺激因子(GM-CSF)、铁调素、人生长激素(hGH)、hGH拮抗剂、艾替班特(icatibant)、胰岛素样生长因子(IGF)-1、白介素1受体拮抗剂(IL-1Ra)、Infestin-4、亲吻促动素、L4F肽、催泪蛋白(Lacritin)、甲状旁腺激素(PTH)、甲状旁腺激素-相关的蛋白质(PTHrP)、PYY、Relamorelin、松弛素、生长抑素、硫氧还蛋白、胸腺素β4、TNF-相关的凋亡-诱导配体(TRAIL)、尿酸氧化酶、尿扩张素、尿鸟苷素(uroguanylin)、甲状旁腺激素片段(例如残基1-34)、全长甲状旁腺激素、促肾上腺皮质激素、Coversin、亲吻促动素、亲吻促动素片段(例如氨基酸残基1-10或氨基酸残基1-54)、膜联蛋白A1-衍生的肽(例如氨基酸残基2-26)、其类似物、衍生物、模拟物、片段、组合或功能变体。在一些实施方案中,本发明提供包括蛋白活性剂的治疗剂和提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为弹性蛋白样肽(ELP)。
可通过多种手段延长蛋白质活性剂的半衰期,包括增加蛋白质活性剂的大小并且因此增加蛋白质治疗剂的水动力学体积、添加经修饰的或非天然的氨基酸、缀合模块(例如聚乙二醇化)、添加合成序列(例如序列,)、来自hCG的羧基末端延伸(CTP)、添加白蛋白结合序列(例如)、白蛋白结合化合物例如脂肪酸的缀合、翻译后修饰如N-糖基化和与其它肽的融合,或与哺乳动物异源蛋白(如白蛋白、转铁蛋白或抗体Fc序列)融合。此类序列描述于美国专利号7,238,667(特别是就白蛋白缀合物而言)、美国专利号7,176,278(特别是就转铁蛋白缀合物而言)和美国专利号5,766,883中。
在一些实施方案中,本发明提供了本发明中公开的一种或多种活性蛋白剂的模拟物、类似物、衍生物、变体或突变体。在一些实施方案中,与天然治疗性肽剂的氨基酸序列相比,模拟物、类似物、衍生物、变体或突变体含有一个或多个氨基酸取代。在一些实施方案中,取代1至20个氨基酸。在一些实施方案中,与天然治疗性肽剂的氨基酸序列相比,模拟物、类似物、衍生物、变体或突变体含有约1、约2、约3、约4、约5、约6、约7、约8、约9或约10个氨基酸取代。在一些实施方案中,与天然治疗性肽剂的氨基酸序列相比,模拟物、类似物、衍生物、变体或突变体含有一个或多个氨基酸缺失。在一些实施方案中,与天然蛋白剂的氨基酸序列相比,缺失1至20个氨基酸。在一些实施方案中,与天然蛋白剂的氨基酸序列相比,模拟物、类似物、衍生物、变体或突变体具有约1、约2、约3、约4、约5、约6、约7、约8、约9或约10个氨基酸缺失。在一些实施方案中,与天然蛋白剂的氨基酸序列相比,从任一末端缺失1至10个氨基酸。在一些实施方案中,与天然蛋白剂的氨基酸序列相比,从两个末端缺失1至10个氨基酸。在一些实施方案中,模拟物、类似物、衍生物、变体或突变体的氨基酸序列与天然蛋白剂的氨基酸序列具有至少约70%的同一性。在一些实施方案中,模拟物、类似物、衍生物、变体或突变体的氨基酸序列与天然蛋白剂的氨基酸序列具有约70%、约80%、约85%、约90%、约95%、约96%、约97%,约98%或约99%的同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1.
在一些实施方案中,本发明提供了本发明中公开的任何两种或更多种活性剂的共配制剂。在一些实施方案中,共配制剂包括两种或更多种肽活性剂和小分子活性剂。在一些实施方案中,共配制剂包括两种或更多种小分子活性剂。在一些实施方案中,共配制剂包括两种或更多种肽活性剂。在一些实施方案中,共配制剂中的一种或多种活性剂不与ELP缀合。在一些实施方案中,共配制剂中的所有活性剂与ELP缀合。
爱帕琳肽
在一些实施方案中,蛋白质活性剂是爱帕琳肽、其类似物、模拟物、衍生物、片段或功能变体。人爱帕琳肽是爱帕琳肽受体(APJ A类G蛋白偶联受体)的内源性配体。爱帕琳肽在几种细胞类型中表达,包括人心肌细胞、内皮细胞和血管平滑肌细胞。爱帕琳肽基因已经在多种物种中鉴定出,包括人、狗、牛、大鼠、小鼠、恒河猴和斑马鱼,且编码77个氨基酸的爱帕琳肽前蛋白原。跨越具有3个外显子的基因组DNA的1726个碱基对,爱帕琳肽基因座在物种之间是高度保守的。在爱帕琳肽前蛋白原加工中,切下对应于爱帕琳肽前蛋白原的残基1-22的信号肽,产生55个氨基酸的爱帕琳肽前蛋白,其被加工成几种活性分子形式,包括爱帕琳肽-12、爱帕琳肽-13、爱帕琳肽-16、爱帕琳肽-17和爱帕琳肽-36(Kawamata等人,2001,Biochim Biophys Acta 1538:162-71)。这些活性分子形式统称为爱帕琳肽,并根据其长度和/或修饰状态命名。全长成熟肽爱帕琳肽-36是衍生自55个氨基酸长的爱帕琳肽前蛋白的36个氨基酸长的肽(Tatemoto等人,1998,Biochem.Biophys.Res.Comm.251:471-476,1998),并且对应于前原蛋白的残基42-77。爱帕琳肽-17和爱帕琳肽-13衍生自爱帕琳肽的羧基(C)-末端。爱帕琳肽-17对应于爱帕琳肽前蛋白的残基61-77。爱帕琳肽-13对应于爱帕琳肽前蛋白的残基65-77。爱帕琳肽蛋白可包括氨基酸衍生物或修饰物。例如,最活跃的同种型是爱帕琳肽-13的焦谷氨酸化形式(pyr-爱帕琳肽13)。
爱帕琳肽是内源性血管扩张剂和强心剂(inotrope),其可通过拮抗肾素-血管紧张素系统降低血压,这可能是通过形成受体异源三聚体实现。
在本发明一些实施方案中,所述活性剂包括提供持续释放的氨基酸序列,其融合或缀合至爱帕琳肽、其模拟物、类似物、衍生物、片段或功能变体。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。在一些实施方案中,所述爱帕琳肽为哺乳动物爱帕琳肽。在一些实施方案中,所述爱帕琳肽为人爱帕琳肽(例如,SEQ ID NO:39),其为全长成熟人爱帕琳肽、爱帕琳肽-36(SEQ ID NO:39)。在其它实施方案中,所述爱帕琳肽为爱帕琳肽-36的截短物,包括,但不限于,爱帕琳肽-16、爱帕琳肽-17(SEQ ID NO:41)、爱帕琳肽-13(SEQ ID NO:43)和爱帕琳肽-12(SEQ ID NO:44)。在一些实施方案中,所述爱帕琳肽包含一个或多个修饰的氨基酸。在一些实施方案中,所述爱帕琳肽包含一个或多个氨基酸衍生物。在一些实施方案中,所述爱帕琳肽为pyr-爱帕琳肽13(SEQ ID NO:42)。
在一些实施方案中,所述爱帕琳肽为哺乳动物爱帕琳肽的功能类似物,包括在爱帕琳肽的N-端和/或C-端截短约1至约30个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、或至多约30个氨基酸。在其它实施方案中,功能变体相对天然或截短序列(例如,SEQ ID NO:39,41,42,43,或44)包含约1至约30个氨基酸插入、缺失和/或取代。例如,相对天然或截短序列(例如,SEQ ID NO:39,41,42,43,或44),功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、或至多约30个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述爱帕琳肽与天然或截短序列(例如,SEQ IDNO:39,41,42,43,或44)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述爱帕琳肽可包含本领域已知的其他化学修饰。在一些实施方案中,爱帕琳肽的功能类似物为Elabella/Toddler或其类似物或衍生物(Yang等人,2015,Trends in Pharmacol.Sci.36:560-567)
在一些实施方案中,所述治疗剂包含融合至爱帕琳肽、其模拟物、类似物、衍生物、片段或功能变体的N-端或C-端的ELP。在一些方面,所述治疗剂包含融合至人爱帕琳肽-36的N-端的ELP(SEQ ID NO:40)。在一些实施方案中,所述爱帕琳肽在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述爱帕琳肽在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在爱帕琳肽的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在爱帕琳肽的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在爱帕琳肽的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,爱帕琳肽的N-端的ELP大于爱帕琳肽的C-端的ELP。在其它实施方案中,爱帕琳肽的C-端的ELP大于在爱帕琳肽的N-端的ELP。
在其他方面,本发明提供通过施用ELP和爱帕琳肽治疗或预防疾病的方法,所述疾病包括但不限于心力衰竭、肺动脉高血压(PAH)、缺血性心脏病、糖尿病、癌症、肥胖症、心血管缺陷或涉及血管发生的病理状况(例如,癌症)。在一些实施方案中,可施用本发明公开的治疗剂以提供作用,包括但不限于血管舒张作用(例如,由内皮一氧化氮合酶(eNOS)介导)、正离子移变效应(例如,由于增加的细胞内钙和增加的肌丝钙敏感性)、保护免受缺血再灌注损伤(例如通过一氧化氮(NO)依赖性和NO非依赖性途径)和APJ受体介导的心脏肥大(例如,β-抑制蛋白介导,而不是G蛋白介导)。该方法包括向需要这种治疗的患者施用包含ELP和爱帕琳肽(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,根据本发明的用爱帕琳肽治疗剂的治疗还可以与一种或多种药理活性物质组合,该药理活性物质例如选自用于治疗和/或预防由各种疾病引起的或与之相关的并发症和病症的药剂,包括但不限于心力衰竭、PAH、缺血性心脏病、糖尿病、癌症、肥胖、心血管缺陷或涉及血管发生的病理状况(例如,癌症)。在另外的实施方案中,根据本发明的用爱帕琳肽治疗剂的治疗可以与一种或多种药理活性物质组合,该药理活性物质例如选自提供效果的药剂,所述效果包括但不限于血管舒张作用(例如,由内皮一氧化氮合酶(eNOS)介导)、正离子移变效应(例如,由于增加的细胞内钙和增加的肌丝钙敏感性)、保护免受缺血再灌注损伤(例如通过一氧化氮(NO)依赖性和NO非依赖性途径)和APJ受体介导的心脏肥大(例如,β-抑制蛋白介导,而不是G蛋白介导)。
精氨酸酶
在一些实施方案中,蛋白质活性剂是精氨酸酶(EC 3.5.3.1;L-精氨酸脒基水解酶)、其同功酶、片段或功能变体。精氨酸酶是尿素循环的35kDa关键酶,其催化L-精氨酸向鸟氨酸和尿素的转化,这是哺乳动物肝脏中尿素形成的最终细胞溶质反应。精氨酸酶具有三个重要功能:尿素的产生、鸟氨酸的产生、以及一氧化氮合酶的底物精氨酸水平的调节(Jenkinson等人,1996,Comp.Biochem.Physiol.114B:107-132;Kanyo等人,1996,Nature383:554-557;Christianson,1997,Prog.Biophys.Molec.Biol.67:217-252)。尿素生产提供了一种以高度可溶、无毒的化合物形式排出氮的机制,从而避免了高氨水平的潜在危险后果。L-鸟氨酸是多胺、精胺和亚精胺的生物合成的前体,其在细胞增殖和分化中具有重要作用。最后,精氨酸酶通过调节组织内存在的精氨酸水平来调节一氧化氮的产生。
通常,精氨酸酶在产生尿素的动物(例如哺乳动物,板鳃类鱼,两栖动物和龟)的肝脏、肾脏和睾丸中表达。在包括人在内的大多数哺乳动物中,精氨酸酶蛋白家族包括主要在肝细胞中表达的同工酶精氨酸酶I和主要在肾和红细胞中表达的精氨酸酶II。
在一些实施方案中,人肝精氨酸酶的缺乏可导致精氨酸血症,其为遗传性常染色体隐性病症,伴有高氨血症,为其中过量精氨酸导致癫痫发作、认知能力受损和神经元损伤的病症。临床上显著的高精氨酸血症由精氨酸酶I基因的突变引起(Cederbaum S.D.等人,1979,Pediat.Res.13:827-833;Cederbaum S.等人,1977,J.Pediatr.90:569-573;MichelV.V.等人,1978,Clin.Genet.13:61-67)。由于精氨酸酶缺乏,精氨酸不能降解为尿素并参与鸟氨酸代谢循环,导致血液精氨酸水平为正常水平的约7至约10倍,脑脊液中精氨酸水平增加,尿量增加,肌酸肝的尿素排泄增加。精氨酸酶I缺乏的患者可表现出痉挛状态、生长迟缓、进行性精神损伤和发作性高氨血症(Cederbaum S.D.等人,1979,Pediat Res 13:827-833;Cederbaum S.D.等人,1977,J.Pediatr 90:569-573;Thomas K.R.和Capecchi M.R.,1987,Cell51:503-512)。
在本发明一些实施方案中,精氨酸酶治疗剂包括融合或缀合至精氨酸酶、其模拟物、类似物、衍生物、片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸剂为ELP。
在一些实施方案中,所述精氨酸酶为哺乳动物精氨酸酶。在一些实施方案中,所述精氨酸酶为精氨酸酶I。在其它实施方案中,所述精氨酸酶为精氨酸酶II。在一些实施方案中,所述精氨酸酶为人精氨酸酶(SEQ ID NO:45)。
在一些实施方案中,所述精氨酸酶为哺乳动物精氨酸酶的功能类似物,包括在精氨酸酶的N-端和/或C-端截短约1至约50个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、或至多约50个氨基酸。在其它实施方案中,功能变体相对天然序列(例如,SEQ IDNO:45)包含约1至约50个氨基酸的插入、缺失和/或取代。例如,功能变体相对天然序列(例如,SEQ ID NO:45)可具有至多约3个氨基酸、约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、或至多约50个氨基酸插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述精氨酸酶与天然序列(例如,SEQ ID NO:45)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述精氨酸酶可包含本领域已知的其他化学修饰。在一些实施方案中,所述精氨酸酶可使用锰作为辅因子,而不是钴。
在一些实施方案中,所述治疗剂包含融合至精氨酸酶、其模拟物、类似物、衍生物、片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至人精氨酸酶的C-端的ELP(SEQ ID NO:46)。在一些实施方案中,所述精氨酸酶是在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述精氨酸酶在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在精氨酸酶的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在精氨酸酶的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在精氨酸酶的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,在精氨酸酶的N-端的ELP大于精氨酸酶的C-端的ELP。在其它实施方案中,在精氨酸酶的C-端的ELP大于在精氨酸酶N-端的ELP。
在其他方面,本发明提供了用于治疗或预防与精氨酸酶基因或精氨酸酶基因表达的缺陷相关或由其引起的疾病的方法,所述疾病例如尿素循环疾病;高血压;低血压;高氨血症;发作性高氨血症;脯氨酸、谷氨酸、一氧化氮和鸟氨酸生物合成缺陷;高精氨酸血症及其相关痉挛;生长迟缓;进行性精神损害;前列腺疾病、前列腺癌、前列腺炎或良性前列腺增生或肥大、前列腺损害;肾脏疾病和肾脏损害;癌症,包括但不限于非霍奇金淋巴瘤,肝癌,黑素瘤或肾细胞癌;自身免疫性疾病;纤维化疾病;勃起功能障碍;肺高血压;动脉粥样硬化;肾病;哮喘;T细胞功能障碍;缺血再灌注损伤;神经退行性疾病;伤口愈合;精氨酸依赖性增生;肿瘤;肝癌;黑色素瘤;肾细胞癌;HCC;或黑素瘤。该方法包括向需要这种治疗的患者施用包含ELP和精氨酸酶(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,根据本发明的用精氨酸酶治疗剂的治疗还可以与一种或多种药理学活性物质组合,该药理学活性物质例如选自用于治疗和/或预防由各种疾病引起或与之相关的并发症和病症的药剂,包括但不限于高血压;低血压;高氨血症;发作性高氨血症;脯氨酸、谷氨酸、一氧化氮和鸟氨酸生物合成缺陷;高精氨酸血症及其相关痉挛;生长迟缓;进行性精神损害;前列腺疾病、前列腺癌、前列腺炎或良性前列腺增生或肥大、前列腺损害;肾脏疾病和肾脏损害;癌症,包括但不限于非霍奇金淋巴瘤,肝癌,黑素瘤或肾细胞癌;自身免疫性疾病;纤维化疾病;勃起功能障碍;肺高血压;动脉粥样硬化;肾病;哮喘;T细胞功能障碍;缺血再灌注损伤;神经退行性疾病;伤口愈合;精氨酸依赖性增生;肿瘤;肝癌;黑色素瘤;肾细胞癌;HCC;或黑素瘤。
C-型利钠肽(CNP)
在一些实施方案中,所述蛋白活性剂为C-型利钠肽(CNP)、其模拟物、类似物、衍生物、片段或功能变体。利钠肽在心血管稳态、利尿、尿钠排泄和血管舒张中起作用。利钠肽家族由三种结构相关肽组成:心钠肽(ANP),脑利钠肽(BNP)和C型利钠肽(CNP)。这些小的单链肽(ANP、BNP和CNP)具有17个氨基酸的环结构(Levin等人,N.Engl.J.Med.,339:863-870(1998))并且在多个生物过程中起重要作用。ANP和BNP主要在心脏的肌细胞内产生,并且在心血管稳态中具有重要作用(Science,252:120-123(1991))。CNP更广泛地表达,包括在中枢神经系统、生殖道、骨和血管内皮中(Hypertension,49:419-426(2007)),并且例如作为骨生长的调节剂、血管扩张剂和强心剂起作用,并有心血管作用。
在人类中,CNP最初由利钠肽前体C(NPPC)基因作为单链126-氨基酸前原多肽产生(Sudoh,T.等人,Biochem.Biophys.Res.Commun.,1990,168:863-870)。去除信号肽产生pro-CNP,并且内切蛋白酶弗林蛋白酶的进一步切割产生活性53-氨基酸肽(CNP-53),其被分泌和再次裂解以产生成熟的22-氨基酸肽(CNP-22)(Wu,J.Biol.Chem.,2003,278:25847-852)。CNP-53和CNP-22的分布不同,CNP-53主要存在于组织中,而CNP-22主要存在于血浆和脑脊液中(J.Alfonzo,Recept.Signal.Transduct.Res.,2006,26:269-297)。CNP的主要生物活性形式是CNP-22。
利钠肽主要通过两种受体起作用:利钠肽受体-A(NPR-A)和利钠肽受体B(NPR-B)。这些受体具有细胞质鸟苷酸环化酶结构域,其在ANP、BNP或CNP结合时被激活并导致细胞内cGMP的积累。CNP-53和CNP-22都与NPR-B类似地结合,它们都能以剂量依赖性和相似的方式诱导cGMP的产生(Yeung,V.T.,Peptides,1996,17:101-106)。第三种受体,NPR-C,以高亲和力结合每个利钠肽,主要用于从细胞外区室捕获肽并将肽沉积到溶酶体中,在那里它们被降解(Maak,T.等人,Science,1987,238:675-678)。
CNP结合并活化NPR-B,导致细胞内环单磷酸鸟苷(cGMP)水平增加。由cGMP产生介导的下游信号传导影响多种生物过程,包括软骨内骨化(控制纵向长骨生长的过程)。
在本发明一些实施方案中,所述治疗剂包括融合或缀合至CNP、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述CNP为哺乳动物CNP。在一些实施方案中,所述CNP为人CNP-53(SEQ ID NO:51)。在其它实施方案中,所述CNP为CNP-22(SEQ ID NO:47)。在其它实施方案中,所述CNP为CNP-37(SEQ ID NO:49)。在其它实施方案中,所述CNP为CNP-39(SEQID NO:52)。
在一些实施方案中,所述CNP为哺乳动物CNP的片段或功能变体,包括在CNP的N-端和/或C-端截短约1至约30个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、或至多约30个氨基酸。在其它实施方案中,功能变体相对天然或截短序列(例如,SEQ IDNO:47、49、51或52)包含约1至约30个氨基酸的插入、缺失和/或取代。例如,相对天然或截短序列(例如,SEQ ID NO:47、49、51或52),功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、或至多约30氨基的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述CNP与天然或截短序列(例如,SEQ ID NO:47、49、51或52)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述CNP可包含本领域已知的其他化学修饰。
在一些方面,治疗剂包含融合至CNP、其片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至CNP-22的N-端的ELP(SEQ ID NO:48)。在另一方面,所述治疗剂包含融合至CNP-37的N-端的ELP(SEQ ID NO:50)。在一些实施方案中,所述治疗剂包含融合至CNP的C-端的ELP(例如SEQ ID NO:57或98)。在一些实施方案中,所述治疗剂包含融合至pro-CNP的ELP(SEQ ID NO:56)。在一些实施方案中,所述CNP在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述CNP在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在CNP的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在CNP的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其它实施方案中,在CNP的C-端和/或N-端的ELP包含少于约40个重复结构单元。在其他方面,在CNP的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,CNP的N-端的ELP大于CNP的C-端的ELP。在其它实施方案中,CNP的C-端的ELP大于在CNP的N-端的ELP。
在一些实施方案中,所述ELP通过接头(SEQ ID NO:83和55)连接至CNP的C-端和/或N-端。在一些实施方案中,所述接头包含三肽GGS序列(SEQ ID NO:87)。在一些方面,所述接头包含三肽GGS(SEQ ID NO:87)的单拷贝。在另一方面,所述接头包含三肽GGS的多个重复体。在一些实施方案中,所述接头包含GGS序列的两个重复体(SEQ ID NO:102)。在一些实施方案中,所述接头包含GGS序列的三个重复体(SEQ ID NO:103)。在一些实施方案中,所述接头包含五肽GGGGS序列(SEQ ID NO:93)。在一些方面,所述接头包含五肽GGGGS(SEQ IDNO:93)的单拷贝。在另一方面,所述接头包含五肽GGGGS的多个重复体。在一些实施方案中,所述接头包含GGGGS序列的两个重复体(SEQ ID NO:104)。在一些实施方案中,所述接头包含GGGGS序列的三个重复体(SEQ ID NO:105)。在一些实施方案中,所述接头包含五肽PAPAP序列(SEQ ID NO:94)。在一些方面,所述接头包含五肽PAPAP的单拷贝。在另一方面,所述接头包含五肽PAPAP的多个重复体。在一些实施方案中,所述接头包含PAPAP序列的两个重复体(SEQ ID NO:106)。在一些实施方案中,所述接头包含PAPAP序列的三个重复体(SEQ IDNO:107)。在一些实施方案中,所述接头包含五肽EAAAK序列(SEQ ID NO:95)。在一些方面,所述接头包含五肽EAAAK的单拷贝。在另一方面,所述接头包含五肽EAAAK的多个重复体。在一些实施方案中,所述接头包含EAAAK序列的两个重复体(SEQ ID NO:108)。在一些实施方案中,所述接头包含EAAAK序列的三个重复体(SEQ ID NO:109)。
在一些实施方案中,所述ELP通过包含蛋白酶识别位点的肽序列连接至CNP的C-端和/或N-端。在一些实施方案中,所述蛋白酶识别位点在体内裂解,从而释放CNP。在一些实施方案中,所述蛋白酶识别位点在注射位点裂解,从而释放CNP。在一些实施方案中,所述蛋白酶识别位点在循环中裂解,从而释放CNP。在一些实施方案中,所述蛋白酶识别位点在邻近生长板的关节裂解,从而在需要的地方释放CNP且最小化副作用。蛋白酶识别位点包括用于Factor Xa(例如IEGR↓、IDGR↓、GR↓)、凝血酶(例如LVPR↓GS、LVPR↓GF)、组织蛋白酶(例如组织蛋白酶K、RKPR↓G、RKLR↓G)、基质金属蛋白酶(MMP)(例如用于MMP1、MMP2、MMP3、MMP7、MMP8和MMP9的PLGL↓WAG“共有”识别序列(Eckhard等人(2016)Matrix Biology 49,37-60))的那些。Chou等人对人组织蛋白酶K的优选切割位点的分析(2006.J.Biol.Chem.281,12824-12832)表明了可使用的替代切割位点,例如P3可为K、G、H或M,P2可为P、I或L,P1可为Q、R或K。
在其他方面,本发明提供了用于治疗或预防疾病的方法,所述疾病包括但不限于与骨生长调节相关的疾病(例如,包括侏儒症和软骨发育不全的骨骼发育不良);幼年特发性关节炎;骨关节炎;心血管疾病;影响心血管内稳态、利尿、尿钠排泄或血管舒张的疾病;中枢神经系统疾病,生殖道疾病;或影响血管内皮的疾病。该方法包括向需要这种治疗的患者施用包含ELP和CNP(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,根据本发明的CNP治疗剂的治疗还可以与一种或多种药理活性物质组合,例如,选自用于治疗和/或预防由各种疾病引起或与之相关的并发症和病症的药剂,包括但不限于影响骨生长调节的疾病(例如,骨骼发育不良,包括侏儒症和软骨发育不全);幼年特发性关节炎;骨关节炎;心血管疾病;影响心血管内稳态、利尿、尿钠排泄或血管舒张的疾病;中枢神经系统疾病、生殖道疾病;或影响血管内皮的疾病。
胰高血糖素样肽(GLP)-1受体拮抗剂
在本发明一些实施方案中,该治疗剂包含融合或缀合至GLP-1受体拮抗剂如缺乏氨基酸1-8的毒晰外泌肽-4、衍生物、类似物,模拟物、其片段或功能变体的ELP成分。
人GLP-1是源自前高血糖素原(preproglucagon)的37个氨基酸残基的肽,其在回肠末端、胰腺和脑中的L-细胞中合成。加工前高血糖素原以产生GLP-1(7-36)酰胺、GLP-1(7-37)和GLP-2,其主要发生在L-细胞中。
在肠L-细胞中加工后,GLP-1被释放到循环中,最显著地是响应于进餐。GLP-1的血浆浓度从约15pmol/L的禁食水平上升至40pmol/L的餐后峰值水平。
在一些方面,本发明的蛋白活性剂为GLP-1受体拮抗剂。在一些实施方案中,所述GLP-1受体拮抗剂为GLP-1的N-端和/或C-端片段。在一些实施方案中,所述GLP-1受体拮抗剂包括氨基酸序列:DVSSYLEGQAAKEFIAWLVKGR(SEQ ID NO:54、64和65),或其片段。在一些方面,GLP-1受体拮抗剂为GLP-1(9-31)(SEQ ID NO:54)。在其它方面,GLP-1受体拮抗剂为GLP-1(9-29)(SEQ ID NO:64)。在其他方面,GLP-1受体拮抗剂为GLP-1-毒晰外泌肽-4(SEQID NO:65)。
在其它实施方案中,所述GLP-1受体拮抗剂为毒晰外泌肽-4的N-端和/或C-端片段。在一些实施方案中,所述GLP-1受体拮抗剂包括以下氨基酸序列:DLSKQMEEEAVRLFIEWLKNGGP(SEQ ID NO:27、28、60、61、62和63),或其片段。在一些实施方案中,所述毒晰外泌肽-4片段包括,但不限于,毒晰外泌肽-4(9-39)(SEQ ID NO:27)、毒晰外泌肽-4(9-31)(SEQ ID NO:28)、毒晰外泌肽-4(9-30)(SEQ ID NO:60)、M-毒晰外泌肽-4(9-39)(SEQ ID NO:62)、M-毒晰外泌肽-4(9-31)(SEQ ID NO:61)、或M-毒晰外泌肽-4(9-30)(SEQ ID NO:63)。
在其它实施方案中,所述GLP-1受体拮抗剂包括氨基酸序列:DVSSYLEGQAAKEFIAWLVKGR(SEQ ID NO:66和67),或其片段。在一些方面,GLP-1受体拮抗剂为Jant-4(9-30)(SEQ ID NO:66)。在另一方面,GLP-1受体拮抗剂为Jant-4(9-39)(SEQ IDNO:67)。
在一些实施方案中,所述GLP-1受体拮抗剂为哺乳动物GLP-1受体拮抗剂。在一些实施方案中,所述GLP-1受体拮抗剂为人GLP-1受体拮抗剂(例如,SEQ ID NO:27、28、54、56、60、61、62、63、64、65、66、或67)。在一些实施方案中,所述GLP-1受体拮抗剂为哺乳动物GLP-1受体拮抗剂的功能类似物,包括在GLP-1受体拮抗剂的N-端和/或C-端截短约1至约30个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、或至多约30个氨基酸。在其它实施方案中,功能变体相对天然或截短序列(例如,SEQ ID NO:27、28、54、56、60、61、62、63、64、65、66、或67)包含约1至约30个氨基酸的插入、缺失和/或取代。例如,相对天然或截短序列(例如,SEQ ID NO:27、28、54、56、60、61、62、63、64、65、66、或67),功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、或至多约30个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述GLP-1受体拮抗剂具有的氨基酸序列与天然或截短序列(例如,SEQ ID NO:27、28、54、56、60、61、62、63、64、65、66、或67)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述GLP-1受体拮抗剂可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至GLP-1受体拮抗剂、其类似物、模拟物、衍生物、片段或功能变体的C-端的ELP。在一些实施方案中,所述治疗剂包含融合至人GLP-1受体拮抗剂(例如,SEQ ID NO:58和59)的N-端的ELP。在一些实施方案中,所述GLP-1受体拮抗剂在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述GLP-1受体拮抗剂在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在GLP-1受体拮抗剂的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在GLP-1受体拮抗剂的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,GLP-1受体拮抗剂的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,GLP-1受体拮抗剂的N-端的ELP大于GLP-1受体拮抗剂的C-端的ELP。在其它实施方案中,GLP-1受体拮抗剂的C-端的ELP大于GLP-1受体拮抗剂的N-端的ELP。
在其他实施方案中,GLP-1受体拮抗剂治疗剂用于治疗疾病,包括但不限于糖尿病(1型或2型);代谢疾病;肥胖;胰岛素分泌过多引起的疾病,包括但不限于与高胰岛素血症相关的低血糖症;胃手术后获得的高胰岛素血症性低血糖;或高胰岛素血症,例如先天性高胰岛素血症或胃手术后获得性高胰岛素血症,例如用于治疗肥胖症的胃手术。该方法包括向需要这种治疗的患者施用包含ELP和GLP-1受体拮抗剂(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,根据本发明的GLP-1受体拮抗剂治疗剂的治疗还可以与一种或多种药理活性物质组合,该药理活性物质例如选自用于治疗和/或预防由疾病引起或与之相关的各种并发症和病症的药剂,包括但不限于糖尿病(1型或2型);代谢疾病;肥胖;胰岛素分泌过多引起的疾病,包括但不限于与高胰岛素血症相关的低血糖症;胃手术后获得的高胰岛素血症性低血糖;或高胰岛素血症,例如先天性高胰岛素血症或胃手术后获得性高胰岛素血症,例如用于治疗肥胖症的胃手术。
胰高血糖素样肽(GLP)-2受体激动剂
在本发明一些实施方案中,所述治疗剂包含融合或缀合至GLP-2受体激动剂、其衍生物、类似物、模拟物、片段或功能变体的ELP。在一些实施方案中,所述GLP-2受体激动剂为GLP-2。
GLP-2是在肠的肠内分泌L细胞和脑干的特定区域中从胰高血糖素原的翻译后加工释放的33-氨基酸肽。它与GLP-1、胃泌酸调节素和肠高血糖素共同分泌,响应于营养摄入。GLP-2在氨基酸序列方面显示出显著的与胰高血糖素和GLP-1的同源性。不同的哺乳动物GLP-2形式也是高度保守的。例如,人GLP-2(hGLP-2)和degu(南美啮齿动物)GLP-2与大鼠GLP-2(rGLP-2)分别有一个和三个氨基酸的不同。GLP-2结合属于II类胰高血糖素分泌素家族的单个G蛋白偶联受体。GLP-2受体位于小肠、结肠和胃中,这些是已知对GLP-2有反应的位点(Yusta等,2000,Gastroenterology,119:744-55)。
在本发明一些实施方案中,所述活性剂包含融合或缀合至GLP-2受体激动剂、其衍生物、类似物、模拟物、片段或功能变体的提供持续释放的氨基酸序列。在本发明一些实施方案中,所述活性剂包含融合或缀合至GLP-2受体激动剂和hGH的提供持续释放的氨基酸序列。在一些实施方案中,所述GLP-2受体激动剂和hGH在提供持续释放的氨基酸序列的不同末端连接。在一些实施方案中,所述GLP-2受体激动剂连接至提供持续释放的氨基酸序列的氨基端,且hGH连接至羧基端。在一些实施方案中,所述hGH连接至提供持续释放的氨基酸序列的氨基端且GLP-2受体激动剂连接至羧基端。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述GLP-2受体激动剂为哺乳动物GLP-2受体激动剂,如人GLP-2受体激动剂。在一些实施方案中,所述GLP-2受体激动剂为人GLP-2肽(SEQ ID NO:68)。在其它实施方案中,所述GLP-2受体激动剂为GLP-2肽类似物,其中GLP-2肽的N-端的2位的丙氨酸(A)已被甘氨酸(G)替代(SEQ ID NO:70)。在一些实施方案中,所述GLP-2受体激动剂包含序列HXDGSFSDEMNTILDNLAARDFINWLIQTKITD(SEQ ID NO:74),其中X为丙氨酸(A)、甘氨酸(G)、亮氨酸(L)、异亮氨酸(I)、或缬氨酸(V)。在一些实施方案中,X为丙氨酸(A)或甘氨酸(G)。
在一些实施方案中,所述GLP-2受体激动剂为哺乳动物GLP-2肽的功能变体,包括在人GLP-2肽的C-端截短约1至约25个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、或至多约25个氨基酸。在其它实施方案中,功能变体相对天然或共有序列(例如,SEQ ID NO:68或74)可包含约1至约25个氨基酸的插入、缺失和/或取代。例如,功能变体相对共有序列(例如,SEQ ID NO:68或74)可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、或至多约25个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用的测试证实或测定。在其它实施方案中,所述GLP-2受体激动剂与天然或共有序列(例如,SEQ ID NO:68或74)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述GLP-2受体激动剂可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至GLP-2受体激动剂、其片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至GLP-2肽的C-端的ELP(SEQID NO:69、71和73)。
在一些实施方案中,所述GLP-2受体激动剂在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述GLP-2受体激动剂在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在GLP-2受体激动剂的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在GLP-2受体激动剂的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在GLP-2受体激动剂的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在一些实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,GLP-2受体激动剂的N-端的ELP大于GLP-2受体激动剂的C-端的ELP。在其它实施方案中,GLP-2受体激动剂的C-端的ELP大于在GLP-2受体激动剂的N-端的ELP。在一些实施方案中,所述ELP通过接头(SEQ IDNO:71和73)连接至GLP-2受体激动剂的C-端和/或N-端。在一些实施方案中,所述接头包含三肽GGS序列(SEQ ID NO:87)。在一些方面,所述接头包含三肽GGS的单拷贝。在另一方面,所述接头包含三肽GGS的多个重复体。在一些实施方案中,所述接头包含GGS序列的两个重复体(SEQ ID NO:102)。在一些实施方案中,所述接头包含GGS序列的三个重复体(SEQ IDNO:103)。在一些实施方案中,所述接头包含五肽GGGGS序列(SEQ ID NO:93)。在一些方面,所述接头包含五肽GGGGS(SEQ ID NO:93)的单拷贝。在另一方面,所述接头包含五肽GGGGS的多个重复体。在一些实施方案中,所述接头包含GGGGS序列的两个重复体(SEQ ID NO:104)。在一些实施方案中,所述接头包含GGGGS序列的三个重复体(SEQ ID NO:105)。在一些实施方案中,所述接头包含五肽PAPAP序列(SEQ ID NO:94)。在一些方面,所述接头包含五肽PAPAP的单拷贝。在另一方面,所述接头包含五肽PAPAP的多个重复体。在一些实施方案中,所述接头包含PAPAP序列的两个重复体(SEQ ID NO:106)。在一些实施方案中,所述接头包含PAPAP序列的三个重复体(SEQ ID NO:107)。在一些实施方案中,所述接头包含五肽EAAAK序列(SEQ ID NO:95)。在一些方面,所述接头包含五肽EAAAK的单拷贝。在另一方面,所述接头包含五肽EAAAK的多个重复体。在一些实施方案中,所述接头包含EAAAK序列的两个重复体(SEQ ID NO:108)。在一些实施方案中,所述接头包含EAAAK序列的三个重复体(SEQ ID NO:109)。
在其它方面,本发明提供治疗或预防肠疾病的方法,包括,但不限于,肠疾病如炎性肠病(IBD),如溃疡性结肠炎(UC)和克罗恩病(CD),或短肠综合征(SBS);化疗-诱导的粘膜炎;化疗-诱导的腹泻;或缺血-再灌注损伤。该方法包括向需要该治疗的患者施用包含ELP和GLP-2受体激动剂(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。在一些实施方案中,用根据本发明的GLP-2受体激动剂的治疗也可与一种或多种药理学活性物质组合,该药理学活性物质例如选自用于治疗和/或预防由不同疾病引起或与之相关的各种并发症和病症的药剂,包括但不限于肠疾病,包括,但不限于,肠疾病如IBD(如UC或CD)或SBS;化疗-诱导的粘膜炎;化疗-诱导的腹泻;或缺血-再灌注损伤。
铁调素(Hepcidin)
在一些实施方案中,活性剂为铁调素(即LEAP-1(肝-表达的抗微生物肽))、其衍生物、类似物、模拟物、片段或功能变体。铁调素是一种8kDa肽激素,由肝细胞响应于炎症或血液中铁水平升高而产生。
在寻找由铁调节的肝特异性基因中鉴定了编码小鼠中的83个氨基酸的前肽原和大鼠和人中的84个氨基酸的前肽原的铁调素cDNA(Pigeon等人,2001,J.Biol.Chem.276:7811(2001))。首先切割24个残基的N端信号肽以产生前铁调素,然后将其进一步加工以产生在血液和尿液中发现的成熟铁调素。在人尿中,主要形式的铁调素含有25个氨基酸,尽管也存在较短的22和20个氨基酸的肽。
人铁调素为25-氨基酸肽(Hep25)。(参见Krause等人,2000,FEBS Lett480:147-150,和Park等人,2001,J.Biol.Chem.276:7806-7810)。铁调素的生物活性的25-氨基酸形式的结构为简单的发夹结构,其具有8个半胱氨酸,其形成4个二硫键(Jordan等人,2009,J.Biol.Chem.284:24155-67)。
铁调素与其受体即铁输出通道铁转运蛋白结合,并引起其内化和降解,从而减少铁转运蛋白介导的铁释放到血液中。内化进一步减少了穿过肠粘膜的铁转运和肝脏和巨噬细胞的摄取。在急性和慢性炎症中,铁调素表达增加,这降低了用于红细胞生成的铁可用性。在一些实施方案中,所述铁调素治疗剂包含融合或缀合至铁调素、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述铁调素为哺乳动物铁调素。在一些实施方案中,所述哺乳动物铁调素为人铁调素(SEQ ID NO:75)。在一些实施方案中,所述哺乳动物铁调素包含铁调素的N-端片段,DTHFPICIF(SEQ ID NO:88),其对活性关键。在一些实施方案中,本发明提供模拟Hep25(生物活性的人25-氨基酸形式)的铁调素活性的肽片段。这种肽称为“微型-铁调素”。
在一些实施方案中,所述铁调素为人铁调素的功能变体,包括在铁调素C-端截短约1至约20个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、或至多约20个氨基酸。在其它实施方案中,相对天然序列(例如,SEQ ID NO:75),功能变体在C-端包含约1至约20个氨基酸的插入、缺失和/或取代。例如,相对天然序列(例如,SEQ ID NO:75),功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、或至多约20个氨基酸的插入、缺失和/或取代。
可以使用任何可用的测定来确认或测定蛋白质活性。如本发明所用,在一些实施方案中,具有“铁调素活性”的化合物表明当施用该化合物时(例如肠胃外注射或口服施用),具有以剂量依赖性和时间依赖性方式降低受试者(例如小鼠或人)中血浆铁浓度的能力。(参见,例如,如Rivera等,2005,Blood,106:2196-2199中所示)。在一些实施方案中,本发明的肽具有体外活性,其通过在表达铁转运蛋白的细胞系中引起铁转运蛋白内化和降解的能力测定,如Nemeth等2006,Blood,107:328-333中所教导。体外活性可以例如通过工程化显示与绿色荧光蛋白融合的铁转运蛋白的细胞的剂量依赖性荧光损失来测量,如Nemeth等,2006,Blood,107:328-33中所教导的。
在一些实施方案中,所述铁调素与天然序列(例如,SEQ ID NO:75)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述铁调素可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至铁调素、其片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至人铁调素的N-端的ELP(SEQ ID NO:76)。在其它实施方案中,所述治疗剂包含融合至人铁调素的C-端的ELP(SEQ ID NO:77)。
在一些实施方案中,所述铁调素在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述铁调素在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在铁调素的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在铁调素的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在铁调素的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,铁调素的N-端的ELP大于铁调素肽的C-端的ELP。在一些实施方案中,铁调素的C-端的ELP大于在铁调素的N-端的ELP。
在其它方面,本发明提供治疗或预防肠疾病的方法,包括,但不限于,铁过载疾病如遗传性血色素沉着病(HH)或铁负荷性贫血;2型血色素沉着病;心脏病如心肌铁沉着病或心力衰竭;引起内分泌损伤的疾病;肝疾病如肝硬化或肝细胞癌;糖尿病;β-地中海贫血;急性严重感染;或真性红细胞增多症。该方法包括向需要该治疗的患者给药包含ELP和铁调素(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,用根据本发明的铁调素治疗剂的治疗也可与一种或多种药理学活性物质组合,该药理学活性物质例如选自用于治疗和/或预防由各种疾病引起或与之相关的各种并发症和病症的药剂,包括但不限于铁过载疾病如遗传性血色素沉着病(HH)或铁负荷性贫血;2型血色素沉着病;心脏病如心肌铁沉着病或心力衰竭;引起内分泌损伤的疾病;肝疾病如肝硬化或肝细胞癌;糖尿病;β-地中海贫血;急性严重感染;或真性红细胞增多症。
胰岛素样生长因子-1(IGF-1)
在一些实施方案中,所述蛋白活性剂为IGF-1、其衍生物、类似物、模拟物、片段或功能变体。IGF-I是存在于血浆和其他体液中以及许多细胞/组织中且包含70个氨基酸的单链肽,包括3个二硫键,并且刺激多种细胞类型的增殖,并介导一些生长激素的作用。
IGF-1具有全身和局部作用,并且主要与不同的特异性结合蛋白结合,其中四种被称为IGFBP1、IGFBP2、IGFBP3和IGFBP4。这些结合蛋白以正面和负面方式调节IGF-1的生物学功能和可用性。
IGF-1主要通过与许多不同细胞类型中暴露于质膜外表面上的IGF-1型受体的相互作用起作用。IGF-1R在许多不同的细胞类型上表达,因此几种生物的组织依赖于IGF-1的作用:肝、肾、肺、肌肉、骨组织和软骨、以及神经组织。
在一些实施方案中,本发明的IGF-1治疗剂包含融合或缀合至IGF-1、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述IGF-1为哺乳动物IGF-1。在一些实施方案中,所述哺乳动物IGF-1为人IGF-1(SEQ ID NO:78)。在一些实施方案中,所述IGF-1为人IGF-1的片段或功能变体,包括在IGF-1的N-端和/或C-端截短约1至约50个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、或至多约50个氨基酸。在其它实施方案中,片段或功能变体相对天然序列(例如,SEQ ID NO:78)包含约1至约50个氨基酸的插入、缺失和/或取代。例如,片段或功能变体相对天然序列(例如,SEQ ID NO:78)可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、或至多约50个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述IGF-1的衍生物、其类似物、模拟物、片段或功能变体与天然序列(例如,SEQ ID NO:78)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSSNeedle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述IGF-1衍生物、其类似物、模拟物、片段或功能变体可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至IGF-1、其衍生物、类似物、模拟物、片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至IGF-1的C-端的ELP(SEQ ID NO:79和80)。
在一些实施方案中,所述IGF-1衍生物、其类似物、模拟物、片段或功能变体在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述IGF-1在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在IGF-1的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在IGF-1的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在IGF-1的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,在IGF-1的N-端的ELP大于IGF-1的C-端的ELP。在其它实施方案中,在IGF-1的C-端的ELP大于在IGF-1的N-端的ELP。
在其他方面,本发明提供了用于治疗或预防疾病的方法,包括但不限于原发性IGF-1缺乏症;神经病;神经系统疾病;癌症;肾脏疾病;肝病;肺部疾病;糖尿病;生长缺陷;对已经开发出针对重组GH的中和抗体的GH基因缺失儿童的治疗;Laron综合征,或Laron型侏儒症;心脏病;或中风。该方法包括向需要这种治疗的患者施用包含ELP和IGF-1(如上所述)的治疗剂。通常,患者可以是人或非人动物患者例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,根据本发明的IGF-1化合物的治疗还可以与化学疗法和放射疗法、以及一种或多种药理活性物质组合,所述药理活性物质例如选自用于治疗和/或预防由各种疾病引起或与之相关的并发症和病症的药剂,包括但不限于原发性IGF-1缺乏症;神经病;神经元疾病;癌症;肾脏疾病;肝病;肺部疾病;糖尿病;生长缺陷;对已经开发出针对重组GH的中和抗体的GH基因缺失儿童的治疗;Laron综合征,或Laron型侏儒症;心脏病;或中风。
尿扩张素
在一些实施方案中,蛋白质活性剂是尿扩张素、其衍生物、类似物、模拟物、片段或功能变体。尿扩张素是32个氨基酸的肽激素,其是利钠肽受体A(NPR-A)激动剂。尿扩张素是心钠肽(ANP)的肾同种型。它是由肾脏中ANP激素原的差异加工形成的,与所有其他组织相反,其中不是在氨基酸98和99之间切割126个氨基酸激素原而形成ANP和利钾尿肽,该激素原在氨基酸95和96之间被切割。在肾中切割ANP激素原导致来自利钾尿肽的C端的4个氨基酸(即苏氨酸-丙氨酸-脯氨酸-精氨酸)连接到ANP的N端。因此,尿扩张素是含有32个氨基酸的肽,其结构与含有28个氨基酸的ANP相同,只是在N端延伸处添加了四个氨基酸(TAPR)。
尿扩张素在肾脏中以生理量产生,差异加工并分泌到尿液中,并形成旁分泌系统的基础,该旁分泌系统在集合管水平调节水和钠的重吸收(Forssmann,W.-G.等人,1998,Histochemistry and Cell Biology 110(4):335-357)。尿扩张素通过增加肾血流量引起利尿。它是响应于平均动脉压增加和远端小管和集合管的细胞增加的血容量而分泌的。对少尿患者(如急性肾衰竭和慢性肾衰竭患者)而言,这一点很重要,因为它会降低血清肌酐并增加尿量。
尿扩张素比ANP更有效并且具有ANP的两倍长的半衰期,这可能是由于尿扩张素的N端对中性肽链内切酶的失活具有抗性。在一些实施方案中,本发明的尿扩张素治疗剂包含融合或缀合至尿扩张素、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述尿扩张素为哺乳动物尿扩张素。在一些实施方案中,所述哺乳动物尿扩张素为人尿扩张素(SEQ ID NO:84)。在一些实施方案中,所述尿扩张素为哺乳动物尿扩张素的衍生物、类似物、模拟物、片段或功能变体,包括在尿扩张素的C-端截短约1至约25个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸,或至多约25个氨基酸。在其它实施方案中,相对天然序列(例如,SEQ ID NO:84),所述尿扩张素、衍生物、类似物、模拟物、片段或功能变体包含约1至约25个氨基酸的插入、缺失和/或取代。例如,相对天然序列(例如,SEQ ID NO:84),尿扩张素、衍生物、类似物、模拟物、片段或功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、或至多约25个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述尿扩张素、衍生物、类似物、模拟物、片段或功能变体与天然序列(例如,SEQ ID NO:84)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS Needle计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,尿扩张素、衍生物、类似物、模拟物、片段或功能变体可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至尿扩张素、其衍生物、类似物、模拟物、片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至人尿扩张素的C-端的ELP(SEQ ID NO:85)。在其它实施方案中,所述治疗剂包含融合至人尿扩张素的N-端的ELP(SEQ ID NO:86)。
在一些实施方案中,所述尿扩张素、衍生物、类似物、模拟物、片段或功能变体在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述尿扩张素、衍生物、类似物、模拟物、片段或功能变体在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在尿扩张素、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在尿扩张素、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在尿扩张素、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,尿扩张素的N-端的ELP大于尿扩张素、衍生物、类似物、模拟物、片段或功能变体的C-端的ELP。在其它实施方案中,尿扩张素的C-端的ELP大于尿扩张素、衍生物、类似物、模拟物、片段或功能变体N-端的ELP。
在其它方面,本发明提供治疗或预防疾病的方法,包括但不限于,心脏病如急性心力衰竭(AHF);或肾病如急性肾衰竭或慢性肾衰竭。该方法包括向需要该治疗的患者施用包含ELP和尿扩张素(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,用根据本发明的尿扩张素的治疗也可与一种或多种药理学活性物质组合,该药理学活性物质包括,但不限于利尿剂和用于治疗和/或预防由多种疾病引起或与之相关的并发症和疾病的药剂,该疾病包括但不限于心脏疾病如AHF;或肾病如急性肾衰竭或慢性肾衰竭。
胸腺素β4
在一些实施方案中,所述蛋白活性剂为胸腺素β4、其衍生物、类似物、模拟物、片段或功能变体。胸腺素是指最初从胸腺中鉴定的生物化学和功能上不同的蛋白质家族,现在已知其存在于许多其他组织中,并且具有多种不同的生理功能。已经在不同物种中鉴定了超过20种β-胸腺素的亚型,并且在人类中已经鉴定出三种β-胸腺素,包括胸腺素β4、胸腺素β10和胸腺素β15,它们都具有显著的氨基酸序列同源性。尽管具有这种同源性,但这些胸腺素β蛋白中的每一种都是具有不同功能的独特基因产物。
胸腺素β4是最丰富的β-胸腺素,是高度保守的水溶性酸性多肽。胸腺素β4最初被鉴定为在体外内皮细胞迁移和分化期间上调的蛋白质。编码胸腺素β-4的哺乳动物基因定位于X染色体。X-连接的人胸腺素β-4具有44个氨基酸,并通过去除第一个甲硫氨酰残基被加工成分子量为4.9kDa的43个氨基酸的肽而逃避X-失活(Girardi,M.等人,2003,Immunology 109:1-7)。胸腺素β-4定位于细胞质和细胞核二者中。胸腺素β-4存在于许多组织中,并具有多种生物学功能。它有效地调节肌动蛋白聚合,刺激组织重塑、细胞分化以及损伤后的细胞和组织愈合,并且还参与许多炎性趋化因子和细胞因子的表达。
在一些实施方案中,本发明的胸腺素β4治疗剂包含融合或缀合至胸腺素β4、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述胸腺素β4、衍生物、类似物、模拟物、片段或功能变体为哺乳动物胸腺素β4。在一些实施方案中,所述哺乳动物胸腺素β4为人胸腺素β4(SEQ ID NO:89)。在一些实施方案中,所述胸腺素β4为哺乳动物胸腺素β4的衍生物、类似物、模拟物、片段或功能变体,包括在胸腺素β4的N-端和/或C-端截短约1至约35个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、或至多约35个氨基酸。在其它实施方案中,胸腺素β4、衍生物、类似物、模拟物、片段或功能变体相对天然序列(例如,SEQ ID NO:89)包含约1至约35个氨基酸的插入、缺失和/或取代。例如,相对天然序列(例如,SEQ ID NO:89),胸腺素β4、衍生物、类似物、模拟物、片段或功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、或至多约35个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述胸腺素β4、衍生物、类似物、模拟物、片段或功能变体与天然序列(例如,SEQ ID NO:89)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS NEEDLE计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述胸腺素β4、衍生物、类似物、模拟物、片段或功能变体可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至胸腺素β4、其衍生物,类似物,模拟物、片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至胸腺素β4的C-端的ELP(SEQ ID NO:90)。
在一些实施方案中,所述胸腺素β4、衍生物、类似物、模拟物、片段或功能变体在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述胸腺素β4、衍生物、类似物、模拟物、片段或功能变体在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在胸腺素β4、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在胸腺素β4、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在胸腺素β4、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含多于约180重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,胸腺素β4、衍生物、类似物、模拟物、片段或功能变体的N-端的ELP大于胸腺素β4的C-端的。在其它实施方案中,胸腺素β4、衍生物、类似物、模拟物、片段或功能变体的C-端的ELP大于N-端的ELP。
在其它方面,本发明提供治疗或预防疾病的方法,该疾病包括,但不限于,心力衰竭;肺高血压;缺血性心脏病;干眼;或肝纤维化。该方法包括向需要该治疗的患者给药包含ELP和胸腺素β4(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,用根据本发明的胸腺素β4的治疗也可与一种或多种药理学活性物质组合,该药理学活性物质例如选自用于治疗和/或预防由多种疾病引起或与之相关的并发症和病症的药剂,该疾病包括,但不限于,心力衰竭;肺高血压;缺血性心脏病;干眼;或肝纤维化。
TRAIL
在一些实施方案中,所述蛋白活性剂为TRAIL(TNF-相关的凋亡-诱导配体)、其衍生物、类似物、模拟物、片段或功能变体。
外源性细胞死亡途径由配体-受体相互作用触发,所述配体-受体相互作用导致细胞内信号传导事件,其最终导致靶细胞死亡(细胞凋亡)。一种这样的配体是肿瘤坏死因子(TNF)超家族、TRAIL或Apo2L的成员(Wiley,S.R.等人,1995,Immunity 3:673-682;Pitti,R.M.等人,1996,J.Biol.Chem.271:12687-12690)。TRAIL是281个氨基酸的II型膜蛋白。其细胞外区域包含氨基酸残基114-281,并且在被蛋白酶切割后,形成20kDa大小的可溶性sTRAIL分子,其也具有生物活性。内源性TRAIL作为同型三聚体存在,这是其生物学功能的关键要求。活化的T淋巴细胞和NK细胞表达高水平的TRAIL。
TRAIL蛋白例如通过结合并激活促凋亡的TRAIL表面受体1和2(TRAIL-R1/R2或DR4和DR5)起作用。TRAIL和sTRAIL都能够通过与靶细胞上存在的TRAIL受体相互作用来触发细胞凋亡。
在一些实施方案中,本发明的TRAIL治疗剂包含融合或缀合至TRAIL、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述TRAIL为哺乳动物TRAIL。在一些实施方案中,所述哺乳动物TRAIL为人TRAIL(SEQ ID NO:91)。在一些实施方案中,所述TRAIL可为哺乳动物TRAIL的衍生物、其类似物、模拟物、片段或功能变体,包括在TRAIL的N-端和/或C-端截短约1至约160个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、至多约50个氨基酸、至多约55个氨基酸、至多约60个氨基酸、至多约65个氨基酸、至多约70个氨基酸、至多约75个氨基酸、至多约80个氨基酸、至多约85个氨基酸、至多约90个氨基酸、至多约95个氨基酸、至多约100个氨基酸、至多约105个氨基酸、至多约110个氨基酸、至多约115个氨基酸、至多约120个氨基酸、至多约125个氨基酸、至多约130个氨基酸、至多约135个氨基酸、至多约140个氨基酸、至多约145个氨基酸、至多约150个氨基酸、至多约155个氨基酸、或至多约160个氨基酸。TRAIL、衍生物、类似物、模拟物、片段或功能变体相对天然序列(例如,SEQ ID NO:91)可包含约1至约160个氨基酸的插入、缺失和/或取代。例如,相对天然序列(例如,SEQ ID NO:91),TRAIL、衍生物、类似物、模拟物、片段或功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、至多约50个氨基酸、至多约55个氨基酸、至多约60个氨基酸、至多约65个氨基酸、至多约70个氨基酸、至多约75个氨基酸、至多约80个氨基酸、至多约85个氨基酸、至多约90个氨基酸、至多约95个氨基酸、至多约100个氨基酸、至多约105个氨基酸、至多约110个氨基酸、至多约115个氨基酸、至多约120个氨基酸、至多约125个氨基酸、至多约130个氨基酸、至多约135个氨基酸、至多约140个氨基酸、至多约145个氨基酸、至多约150个氨基酸、至多约155个氨基酸、或至多约160个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述TRAIL、衍生物、类似物、模拟物、片段或功能变体与天然序列(例如,SEQID NO:91)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS NEEDLE计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述TRAIL、衍生物、类似物、模拟物、片段或功能变体可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至TRAIL、其衍生物、类似物、模拟物、片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至TRAIL(SEQID NO:92)的N-端的ELP。
在一些实施方案中,所述TRAIL、衍生物、类似物、模拟物、片段或功能变体在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述TRAIL、衍生物、类似物、模拟物、片段或功能变体在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在TRAIL、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在TRAIL、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在TRAIL、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,TRAIL、衍生物、类似物、模拟物、片段或功能变体的N-端的ELP大于C-端的ELP。在其它实施方案中,在TRAIL的C-端的ELP大于N-端的ELP。
在其它方面,本发明提供治疗或预防疾病的方法,所述疾病包括,但不限于,肿瘤发生和各种类型的癌症;非酒精性脂肪肝疾病(NAFLD);非酒精性脂肪肝炎(NASH);肝硬化;由于复发性丙肝病毒(HCV)感染引起的原位肝移植后(POLT)接受者中的移植后肝纤维化或肝硬化(POLT);胰腺纤维化。该方法包括向需要该治疗的患者施用包含ELP和TRAIL(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,用根据本发明的TRAIL的治疗也可与化学疗法或放射治疗组合。在其它实施方案中,所述用根据本发明的TRAIL的治疗也可与一种或多种药理学活性物质组合,该药理学活性物质例如选自用于治疗和/或预防与多种疾病相关的并发症和病症的药剂,该疾病包括但不限于肿瘤发生和各种类型的癌症;非酒精性脂肪肝疾病(NAFLD);非酒精性脂肪肝炎(NASH);肝硬化;由于复发性丙肝病毒(HCV)感染引起的原位肝移植后(POLT)接受者中的移植后肝纤维化或肝硬化(POLT);胰腺纤维化。
成纤维细胞生长因子21(FGF21)
成纤维细胞生长因子21(FGF21)是FGF家族的成员,其对动物的脂质水平、体重和葡萄糖代谢产生有益效果。已显示转基因小鼠中FGF21的过表达导致葡萄糖和甘油三酯水平降低,以及对饮食诱导的肥胖的抗性(Kharitonenkov等人(2005),J.Clin.Invest.115;1627-1635)。向啮齿动物和灵长类动物施用外源FGF21导致血糖水平正常化、甘油三酯和胆固醇水平降低、葡萄糖耐受性改善和胰岛素敏感性改善(Kharitonenkov等人(2007),Endocrinol.48:774-781)。已经显示在实验动物模型中施用FGF21通过增加能量消耗、身体活动和代谢速率来减少体重和体脂(Long和Kharitonenkov(2011)Biochim.Biophys.Acta1812:791-795)。
FGF21信号传导通过其与包含βKlotho(KLB)和三种不同FGF受体之一(FGFR1c、FGFR2c或FGFR3c)的受体复合物的相互作用介导(Ogawa等人(2007),Proc.Natl.Acad.Sci.USA 104:7432-7437;Suzuki等人(2008),Mol.Endocrinol.22:1006-1014)。据信体内FGF21信号传导的主要功能性受体是KLB/FGFR1c复合物(该复合物在本发明中称为“FGF21R”)。
已经提出FGF21信号传导的药理学活化用于治疗人类的各种疾病和病症,包括2型糖尿病、肥胖症、血脂异常、非酒精性脂肪肝病(非酒精性脂肪肝炎,NASH)和其他代谢病症(Gimeno和Moller(2014)Trends Endocrinol.Metab.25,303-311)。在患有2型糖尿病和肥胖症的患者的临床试验中评估了FGF类似物LY2405319(Kharitonenkov等人(2013)PLOSOne,8,e58575)(Gaich等人(2013)Cell Metabolism18,333-340)。Hecht等人(2012,PLOSOne,7(11):e49345)开发了与人IgG1的Fc结构域融合的长效FGF21类似物。
在一些实施方案中,本发明的FGF21治疗剂包含融合或缀合至FGF21、其片段或功能变体的提供持续释放的氨基酸序列。在一些实施方案中,所述提供持续释放的氨基酸序列为ELP。
在一些实施方案中,所述FGF21为哺乳动物FGF21。在一些实施方案中,所述哺乳动物FGF21为人FGF21(SEQ ID NO:110)。在一些实施方案中,所述FGF21可为哺乳动物FGF21的衍生物、其类似物、模拟物、片段或功能变体,包括在FGF21的N-端和/或C-端截短约1至约160个氨基酸的功能片段,包括,例如,截短至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、至多约50个氨基酸、至多约55个氨基酸、至多约60个氨基酸、至多约65个氨基酸、至多约70个氨基酸、至多约75个氨基酸、至多约80个氨基酸、至多约85个氨基酸、至多约90个氨基酸、至多约95个氨基酸、至多约100个氨基酸、至多约105个氨基酸、至多约110个氨基酸、至多约115个氨基酸、至多约120个氨基酸、至多约125个氨基酸、至多约130个氨基酸、至多约135个氨基酸、至多约140个氨基酸、至多约145个氨基酸、至多约150个氨基酸、至多约155个氨基酸、或至多约160个氨基酸。FGF21、衍生物、类似物、模拟物、片段或功能变体相对天然序列(例如,SEQ ID NO:110)可包含约1至约160个氨基酸的插入、缺失和/或取代。例如,相对天然序列(例如,SEQ ID NO:110),FGF21、衍生物、类似物、模拟物、片段或功能变体可具有至多约3个氨基酸、至多约5个氨基酸、至多约10个氨基酸、至多约15个氨基酸、至多约20个氨基酸、至多约25个氨基酸、至多约30个氨基酸、至多约35个氨基酸、至多约40个氨基酸、至多约45个氨基酸、至多约50个氨基酸、至多约55个氨基酸、至多约60个氨基酸、至多约65个氨基酸、至多约70个氨基酸、至多约75个氨基酸、至多约80个氨基酸、至多约85个氨基酸、至多约90个氨基酸、至多约95个氨基酸、至多约100个氨基酸、至多约105个氨基酸、至多约110个氨基酸、至多约115个氨基酸、至多约120个氨基酸、至多约125个氨基酸、至多约130个氨基酸、至多约135个氨基酸、至多约140个氨基酸、至多约145个氨基酸、至多约150个氨基酸、至多约155个氨基酸、或至多约160个氨基酸的插入、缺失和/或取代。蛋白质活性可使用任何可用测试证实或测定。在其它实施方案中,所述FGF21、衍生物、类似物、模拟物、片段或功能变体与天然序列(例如,SEQID NO:110)具有至少约75%同一性、约80%同一性、约90%同一性、约95%同一性、约96%同一性、约97%同一性、约98%同一性、或约99%同一性。百分比同一性可使用比对程序EMBOSS NEEDLE计算,其可获自http://www.ebi.ac.uk/Tools/psa/emboss_needle/。以下默认参数可用于成对比对:蛋白质权重矩阵=BLOSUM62;空位开放=10;空位延伸=0.1。在一些实施方案中,所述TRAIL、衍生物、类似物、模拟物、片段或功能变体可包含本领域已知的其他化学修饰。
在一些实施方案中,所述治疗剂包含融合至FGF21、其衍生物、类似物、模拟物、片段或功能变体的N-端或C-端的ELP。在一些实施方案中,所述治疗剂包含融合至FGF21的N-端的ELP(SEQ ID NO:110)。
在一些实施方案中,所述FGF21、衍生物、类似物、模拟物、片段或功能变体在具有多于一个ELP序列的融合蛋白中。在一些实施方案中,所述FGF21、衍生物、类似物、模拟物、片段或功能变体在N-和C-端二者具有一个或多个ELP。在一些实施方案中,在FGF21、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含约90至约180个重复结构单元。在其它实施方案中,在FGF21、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含少于约90个重复结构单元。在其他方面,在FGF21、衍生物、类似物、模拟物、片段或功能变体的C-端和/或N-端的ELP包含多于约180个重复结构单元。在一些实施方案中,在N-和C-端的两个或更多个ELP大小近似相同。在其它实施方案中,在N-和C-端的两个或更多个ELP大小不同。在一些实施方案中,FGF21、衍生物、类似物、模拟物、片段或功能变体的N-端的ELP大于C-端的ELP。在其它实施方案中,FGF21的C-端的ELP大于N-端的ELP。
在一些实施方案中,所述治疗剂包含融合至FGF21、其衍生物、类似物、模拟物、片段或功能变体的N-端的ELP和融合至ELP的N-端的GLP-1激动剂(SEQ ID NO:133和134)。该治疗剂结合了FGF21和GLP-1二者活性的益处以治疗糖尿病、肥胖症和相关病症。
在其它方面,本发明提供治疗或预防疾病的方法,该疾病包括,但不限于,肿瘤发生和各种类型的癌症;非酒精性脂肪肝疾病(NAFLD);非酒精性脂肪肝炎(NASH);肝硬化;由于复发性丙肝病毒(HCV)感染引起的原位肝移植后(POLT)接受者中的移植后肝纤维化或肝硬化(POLT);胰腺纤维化。该方法包括向需要该治疗的患者施用包含ELP和FGF21(如上所述)的治疗剂。通常,患者可以是人或非人动物患者(例如,狗、猫、牛或马)。优选地,患者是人。
在一些实施方案中,用根据本发明的FGF21的治疗也可与一种或多种药理学活性物质组合,该药理学活性物质例如选自用于治疗和/或预防与多种疾病相关的并发症和病症的药剂,该疾病包括但不限于肿瘤发生和各种类型的癌症;非酒精性脂肪肝疾病(NAFLD);非酒精性脂肪肝炎(NASH);肝硬化;由于复发性丙肝病毒(HCV)感染引起的原位肝移植后(POLT)接受者中的移植后肝纤维化或肝硬化(POLT);胰腺纤维化。
制剂
本发明提供持续释放制剂,其包含本发明中公开的治疗剂和一种或多种药学可接受赋形剂和/或稀释剂。例如,此类赋形剂包括盐和可起作用以稳定氢键键合的其它赋形剂。可使用本领域已知的任何合适的赋形剂。示例性赋形剂包括但不限于氨基酸,如组氨酸、甘氨酸或精氨酸;甘油;糖,如蔗糖;表面活性剂如聚山梨酯20和聚山梨酯80;柠檬酸;柠檬酸钠;抗氧化剂;盐,包括碱土金属盐,如钠、钾和钙盐;抗衡离子,如氯化物和磷酸盐;糖醇(例如甘露醇);防腐剂;糖醇(例如甘露醇,山梨醇);和缓冲剂。示例性的盐包括氯化钠、氯化钾、氯化镁、氯化钙、磷酸氢二钠、磷酸二氢钠、磷酸钠和磷酸钾。
在足以在体温(例如,37℃,或在一些实施方案中为34至36℃)实现基质形成的pH、离子强度且通常赋形剂存在下配制治疗剂。通常制备治疗剂成使得其在贮存条件下不形成基质。可冷冻贮存、冷藏或室温贮存制剂。贮存条件一般低于制剂的转变温度,如小于约32℃、或小于约30℃、或小于约27℃、或小于约25℃、或小于约20℃、或小于约15℃。例如,制剂可与血液等张或具有模拟生理条件的离子强度。例如,制剂具有的离子强度可为至少25mM氯化钠的离子强度、或至少30mM氯化钠的离子强度、或至少40mM氯化钠的离子强度、或至少50mM的离子强度、或至少75mM氯化钠的离子强度、或至少100mM氯化钠的离子强度、或至少150mM氯化钠的离子强度。在一些实施方案中,制剂具有与0.9%盐水(154mM氯化钠)的离子强度等同的离子强度。
在一些实施方案中,制剂在贮存条件下是稳定的。储存条件可为用于稳定储存制剂的任何条件。在一些实施方案中,所述制剂被冷藏。在一些实施方案中,所述制剂被冷冻。在一些实施方案中,所述储存条件包括低于约30℃的温度。在一些实施方案中,所述储存条件包括约2℃至约8℃的温度。在一些实施方案中,所述储存条件包括低于0℃的温度。在一些实施方案中,所述储存条件包括约-15℃至约-80℃的温度。
可使用本领域中任何适当的手段测量稳定性。通常,稳定的制剂是显示降解产物或杂质的增加小于5%的制剂。在一些实施方案中,制剂在贮存条件下稳定至少约1个月、至少约2个月、至少约3个月、至少约4个月、至少约5个月、至少约6个月或至少约1年或更久。在一些实施方案中,制剂在2-8℃稳定至少约1个月、至少约2个月、至少约3个月、至少约4个月、至少约5个月、至少约6个月、至少约1年或至少约2年或更久。在一些实施方案中,所述制剂在25℃稳定至少约1个月、至少约2个月、至少约3个月、至少约4个月、至少约5个月、至少约6个月、至少约一年,或至少约两年或更久。在一些实施方案中,所述制剂在-15℃至约-80℃稳定至少约1个月、至少约2个月、至少约3个月、至少约4个月、至少约5个月、至少约6个月、至少约一年,或至少约两年或更久。
在一些实施方案中,所述制剂包含氯化钙、氯化镁、氯化钾、磷酸二氢钾、氯化钠、磷酸氢二钠、磷酸二氢钠、组氨酸、精氨酸、甘氨酸、甘油、抗微生物防腐剂(例如间甲酚)、张力调节剂(例如甘露醇)、冰醋酸、乙酸钠三水合物;蔗糖、磷酸二氢钠一水合物、磷酸氢二钠七水合物、锌、间甲酚、苯酚、山梨醇、聚山梨酯80、和聚山梨酯20中两种或更多种。
在一些实施方案中,制剂包含约10mM至约100mM组氨酸范围的组氨酸或另一种氨基酸。在一些实施方案中,制剂包含约10mM至约30mM组氨酸范围的组氨酸或另一种氨基酸。在一些实施方案中,制剂包含约15mM至约25mM组氨酸范围的组氨酸或另一种氨基酸。在一些实施方案中,制剂包含约10mM至约165mM NaCl范围的NaCl。在一些实施方案中,制剂包含约50mM至约165mM NaCl。在一些实施方案中,制剂包含约54mM至约162mM NaCl。在一些实施方案中,制剂包含约110mM至约162mM NaCl。在一些实施方案中,制剂包含约1mM至约20mM范围的磷酸钠。在一些实施方案中,制剂包含约5mM至约15mM范围的磷酸钠。在一些实施方案中,制剂包含约2mM至约10mM范围的磷酸二氢钠。在一些实施方案中,制剂包含约4mM至约8mM范围的磷酸二氢钠。在一些实施方案中,制剂包含约1mM至约10mM范围的磷酸氢二钠。在一些实施方案中,制剂包含约2mM至约7mM范围的磷酸氢二钠。在一些实施方案中,制剂包含约2mM至约5mM范围的磷酸氢二钠。在一些实施方案中,所述制剂包括约0.01%至约0.2%范围的聚山梨酯20。在一些实施方案中,制剂包含约0.01%至约0.2%范围的聚山梨酯80。在一些实施方案中,制剂包括磷酸钠、氯化钠、磷酸二氢钠、磷酸氢二钠和聚山梨酯20。在一些实施方案中,制剂包含约10mM磷酸钠(约7mM磷酸二氢钠和约3mM磷酸氢二钠)、约110mM氯化钠和约0.1%聚山梨酯20。
在一些实施方案中,在生理pH配制制剂。在一些实施方案中,在约5.5至约7.5范围内的pH配制制剂。在一些实施方案中,在约6.0至约7.0范围内的pH配制制剂。在一些实施方案中,在约6.5至约7.0范围内的pH配制制剂。在一些实施方案中,与在较高pH的制剂相比,具有较低pH的制剂表现改善的制剂稳定性。在一些实施方案中,与具有pH约7.0的制剂相比,具有pH约6.5的制剂表现改善的稳定性。在一些实施方案中,与具有pH约6.5的制剂相比,具有pH约6.0的制剂表现改善的稳定性。在一些实施方案中,与在较高pH的制剂相比,具有较低pH的制剂维持较高的单体百分比。在一些实施方案中,与具有pH约7.0的制剂相比,具有pH约6.5的制剂维持较高的单体百分比。在一些实施方案中,与具有pH约6.5的制剂相比,具有pH约6.0的制剂维持较高的单体百分比。
定制制剂中治疗剂的蛋白质浓度以在施用温度驱动基质的形成。例如,较高的蛋白质浓度有助于驱动基质的形成,并且为此目的需要的蛋白质浓度根据所使用的ELP系列而变化。例如,在使用ELP 1-120或具有相当转变温度的氨基酸序列的实施方案中,蛋白质以约1mg/mL至约200mg/mL的范围存在,或以约30mg/mL至约150mg/mL的范围存在。在使用ELP 4-120或具有相当的转变温度的氨基酸序列的实施方案中,蛋白质以约0.005mg/mL至约10mg/mL的范围存在,或以约0.01mg/mL至约5mg/mL的范围存在。
在一些实施方案中,治疗剂可以约0.5mg/mL至约200mg/mL的范围存在,或者以约30mg/mL至约150mg/mL的范围存在。在一些实施方案中,治疗剂以约50mg/mL至约125mg/mL的范围,或约75mg/mL至约110mg/mL的范围存在。在一些实施方案中,治疗剂以约100mg/mL的浓度存在。
在一些方面,本发明提供了用于递送本发明中公开的活性剂的持续释放方案的方法。该方法包括将本发明中所述的药物组合物施用于需要的受试者,其中每月施用约1至约8次药物组合物。在一些实施方案中,每月施用约1次、约2次、约3次、和/或约4次药物组合物。在一些实施方案中,每周施用药物组合物。在一些实施方案中,每天施用药物组合物。在一些实施方案中,每周施用一次至三次药物组合物。在一些实施方案中,每两周施用一次药物组合物。在一些实施方案中,每月施用一至两次药物组合物。在具体实施方案中,每月施用约1次药物组合物。在一些实施方案中,每2个月约一次、每3个月约一次、每4个月约一次、每5个月约一次、和/或每6个月约一次施用药物组合物。药物组合物可以预填充笔或注射器的形式包装,用于每周一次、每周两次、或每月一次至八次施用,或者备选地填充于常规小瓶等。
在一些实施方案中,约每月施用制剂,并且可皮下或肌肉内施用。在一些实施方案中,约每周施用制剂,并且可皮下或肌肉内施用。在一些实施方案中,施用部位不是病理部位,例如不是意图的作用部位。
在一些实施方案中,长期施用本发明中公开的药物组合物。在一些实施方案中,将本发明中公开的药物组合物施用达约6个月、约7个月、约8个月、约9个月、约10个月、约11个月、约1年、约2年、约3年、约4年、约5年、约10年或更久。可以本发明中公开的任何需要的剂量和/或频率施用药物组合物。
在一些实施方案中,施用本发明中公开的药物组合物,直到疾病或病症症状改善。在一些实施方案中,施用本发明中公开的药物组合物,直到疾病或病症症状减轻、延迟和/或治愈。
在一些实施方案中,在患者开始表现一种或多种疾病或病症症状前施用本发明中公开的药物组合物。在一些实施方案中,在疾病或病症症状发作时施用本发明中公开的药物组合物。
治疗剂通常配制用于“全身递送”,这意味着不将药剂局部递送到病理部位或作用部位。相反,从注射部位将药剂吸收到血流中,在那里药剂全身性地起作用或经由循环转运到作用部位。可通过任何已知途径施用治疗剂,例如口服、静脉内、肌肉内、鼻、皮下、阴道内和直肠内施用。在一些实施方案中,制剂通常用于皮下施用。在一些实施方案中,药代动力学(PK)参数在皮下施用药剂时是延长的。在一些实施方案中,融合蛋白的半衰期是延长的。在一些实施方案中,与其它手段(例如静脉内)施用的药剂相比,当皮下施用药剂时PK参数是延长的。在一些实施方案中,与通过其它手段(例如静脉内)施用的药剂相比,当在皮下施用药剂时药剂的贮库是延长的。通过提供从注射部位的缓慢吸收,可控制肾清除和降解,由此实现期望的PK概况。
有利地,组合物由于活性剂的持续释放而提供延长的药代动力学暴露。在具体的方面,可在施用后约10小时、约24小时、约48小时或约72小时达到最大暴露水平;通常在施用后约10小时至约48小时达到最大暴露水平。在达到最大暴露水平后,组合物可实现持续的释放速率,由此获得最大水平的相当大百分比达一段时间。例如,持续率(sustainedrate)可为最大暴露水平的约50%、约60%、约70%、约80%、约90%或约100%。用于维持持续率的示例性时间段是在达到最大暴露水平后约3天、约4天、约5天、约6天、约1周、约2周、约4周、约6周、或约8周。随后,持续率可降低到降低的暴露率。此类降低的暴露率可为最大暴露水平的约5%、约10%、约20%、约30%、约40%、约50%、或约60%。例如,在一个实施方案(PE0256)中,在约1-2天内获得1000ng/mL的最大暴露水平。在此时段后,维持最高暴露水平的约70-100%的持续率,直到约10-12日,其后对于研究的剩余部分获得从约60%降低至约10%的降低的暴露率。
在各种实施方案中,活性剂的血浆浓度在多次施用,如至少2、至少约5或至少约10次制剂施用的过程内不改变超过约20倍、或约10倍、或约5倍、或约3倍。在一些实施方案中,活性剂的血浆浓度在每次施用之间不改变超过约20倍、或约10倍、或约5倍、或约3倍。在一些实施方案中,在达到稳定状态前(例如在约3至约4次施用后)有一些积累。施用是基本上均匀分隔的,如例如约每天、或每周约一次、或每月一次至约五次,或每两个月约一次、或每三个月约一次。在其它实施方案中,可在几次施用中稳定增加剂量,因此在5次或更多次施用后达到稳定状态。
本发明中公开的药物组合物可比未融合或未缀合的对应物以更小剂量和/或更低频率施用。虽然本领域技术人员可在每种情况下确定期望的剂量,但是用于实现治疗益处的治疗剂的合适剂量可例如在每剂约1微克(μg)至约100毫克(mg)/千克接受者体重的范围内,优选在每剂约10μg至约50mg/千克体重的范围内,最优选在每剂约10μg至约50mg/千克体重的范围内。在一些实施方案中,以低剂量施用药物组合物。在一些实施方案中,以每剂1mg/千克体重至每剂约9mg/千克体重的剂量施用药物组合物。在一些实施方案中,以每剂约1mg/千克体重、每剂约3mg/千克体重、和/或每剂约9mg/千克体重施用药物组合物。期望的剂量可作为一剂或一整天以合适的间隔施用的两个或更多个亚剂量呈现。可以单位剂量形式施用这些亚剂量,所述单位剂量形式例如每单位剂量形式含有约10μg至约1000mg,优选约50μg至约500mg,最优选约50μg至约250mg的活性成分。或者,如果接受者的状况如此需要,则所述剂量可作为连续输注施用。
在一些实施方案中,受试者是人,但在其它实施方案中可为非人哺乳动物,例如驯养的宠物(例如狗或猫)或家畜或农场动物(例如马、牛、羊或猪)。
应当理解,为了方便贯穿本发明使用单独形式如“一个”、“一种”和“该/所述”,然而,除非在上以下或明确叙述另有指示的情况下,单数形式意图包括复数。所有数值范围应当理解为包括数值范围内的每个数值点,并应当分别解释为个别记载了每个数值点。涉及相同组分或特性的所有范围的端点是包含性的,并且意图可独立组合。
当与提及的数字指示结合使用时,术语“约”表示提及的数字加上或减去所提及数字的至多10%。例如,语言“约50”覆盖45到55的范围。
如本发明中使用,术语“包括”及其变型意图是非限制性的,使得列表中的项的记载不排除也可以用于此技术的材料、组合物、装置和方法中的其它类似的项。类似地,术语“可”和“能够”及其变型意图是非限制性的,使得实施方案可以或可能包括一些元件或特征的叙述不排除不含那些元件或特征的本技术的其它实施方案。虽然在本发明中使用开放式术语“包括”作为术语诸如包含、含有或具有的同义词来描述和要求保护本发明,但是本技术或其实施方案可备选使用更为限制性的术语,如“由记载的成分组成”或“基本上由记载的成分组成”来描述。
如本发明中使用,“半衰期”(其通常指体内半衰期或循环半衰期)是发生活性剂生物活性的50%降低所需的时间段。在一些实施方案中,该术语包括延长的暴露和长半衰期两者(例如,与未缀合肽相比,从注射部位的缓慢摄取和清除延迟两者)。
除非另有定义,否则本发明中的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。虽然与本发明所描述的方法和材料类似或等同的任何方法和材料可用于本发明的实践或测试,但是本发明描述了优选的方法和材料。
除非另有定义,否则本发明中的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。虽然与本发明所描述的方法和材料类似或等同的任何方法和材料可用于本发明的实践或测试,但是本发明描述了优选的方法和材料。
本发明通过以下非限制性实施例进一步说明。
实施例
实施例1–CNP ELP构建体的制备
合成编码37个氨基酸形式的CNP序列的DNA,用限制酶BglI/EcoRI消化,然后亚克隆到质粒pPE0003中以提供质粒pPE0493,将CNP序列置于ELP 1-120序列的C端。
合成编码37个氨基酸形式的CNP序列的DNA,用限制酶XbaI和BsrGI消化,然后亚克隆到用XbaI和Acc65I切割的质粒pPE0003以提供质粒pPE0531,将CNP序列置于ELP 1-120序列的N端。
合成编码37个氨基酸形式的CNP序列的DNA,以包含甘氨酸和丝氨酸重复接头(Gly-Gly-Ser-Gly-Gly-Ser)。将其用限制酶XbaI和BsrGI消化,然后亚克隆到用XbaI和Acc65I切割的质粒pPE0003以提供质粒pPE0552,将CNP序列置于ELP 1-120序列的N端,其中接头位于两者之间。
合成编码22个氨基酸形式的CNP序列的DNA,用限制酶BglI和EcoRI消化,然后亚克隆到质粒pPE0003以提供质粒pPE0514,将CNP序列置于ELP 1-120序列的C-端。
合成编码22个氨基酸形式的CNP序列的DNA,用限制酶XbaI和BsrGI消化,然后亚克隆到用XbaI和Acc65I切割的质粒pPE0003以提供质粒pPE0550,将CNP序列置于ELP 1-120序列的N-端。
合成编码22个氨基酸形式的CNP序列的DNA,其包含甘氨酸和丝氨酸重复接头(Gly-Gly-Ser-Gly-Gly-Ser)。将其用限制酶XbaI和BsrGI消化,然后亚克隆到用XbaI和Acc65I切割的质粒pPE0003以提供质粒pPE0565,将CNP序列置于ELP 1-120序列的N-端,其中接头位于两者之间。
实施例2–CNP构建体的功效确定
使用表达B型利尿钠受体(NPRB)的原代子宫成纤维细胞和cGMP荧光测定试剂盒(CatchPoint,Molecular Devices,Sunnyvale,CA)证明了实施例1中描述的纯化的CNP构建体的效力。当受体被激活时,它会在细胞内产生cGMP。裂解这些细胞并通过cGMP的竞争性免疫测定法检测cGMP的量。每个样品中的cGMP与辣根过氧化物酶(HRP)标记的cGMP缀合物竞争抗cGMP抗体上的结合位点。在不存在cGMP的情况下,大多数缀合物与抗体结合。增加cGMP的浓度竞争性地降低了结合的缀合物的量,降低了测量的HRP活性。
在测定前一天,将原代子宫成纤维细胞接种在96孔组织培养板上,并在37℃、5%CO2下孵育过夜。第二天,在Dulbecco磷酸盐缓冲盐水(DPBS)中制备CNP构建体的连续稀释液。用Krebs Ringer碳酸氢盐缓冲液(KRB)冲洗细胞,然后在室温下与2mM 3-异丁基-1-甲基黄嘌呤(IBMX)在KRB中温育10分钟以防止cGMP的降解。然后将样品的连续稀释液一式两份加入板中,并将板在37℃、5%CO2下温育40分钟。然后将细胞裂解缓冲液加入每个孔中以裂解细胞并释放cGMP。然后将这些样品转移到cGMP测定板中。将抗cGMP抗体和HRP-cGMP均加入测定板中并在室温下温育2小时。然后用cGMP洗涤缓冲液洗涤板。洗涤后,将信号灯红色底物(stoplight red substrate)加入每个孔中,并将板在室温下温育1小时。然后在具有530nm激发、590nm发射和570nm截止的荧光板读数器上读板。
其中CNP位于融合蛋白的N末端的构建体比CNP位于C末端的构建体更有效。最有效的构建体是PE0552,其效力为CNP肽的约30分之一。见图1A-B。
在正常小鼠(品系FVB/nj)中将PE0552构建体每周皮下注射三次,持续长达五周。在实验开始时小鼠为3-5周龄。通过测量每周给药后的尾长、鼻至肛门的长度和鼻至尾的长度来确定对小鼠线性生长的影响,与注射生理盐水的对照组相比。图2A-C显示PE0552的两个剂量水平导致更快的线性生长速率。.
实施例3–蛋白酶-可裂解的CNP ELP构建体的制备
合成了五种不同的基因,每种基因含有37个氨基酸形式的CNP序列和五个不同蛋白酶切割位点之一(表4)。
用限制酶XbaI/BsrGI消化每个基因序列,然后亚克隆到用XbaI/Acc65i消化的质粒pPE0003,得到质粒pPE9206、pPE9216、pPE9306、pPE9316和pPE9326。这些融合将CNP序列置于ELP 1-120序列的N末端,两者之间具有不同的蛋白酶敏感位点,以使得能够切割以在体内释放CNP序列。
利用实施例2所述的表达B型利尿钠受体(NPRB)的原代子宫成纤维细胞证明了实施例3中描述的纯化的CNP构建体的效力。与未处理的构建体相比,蛋白酶敏感的CNP ELP构建体的预处理增加了效力,这是由于释放了CNP部分。
每天在正常小鼠(品系FVB/nj)中注射上述构建体达三周。在实验开始时小鼠为3周龄。通过测量每周给药后的尾长、鼻至肛门的长度和鼻至尾的长度来确定对小鼠线性生长的影响,与注射生理盐水的对照组相比。图3A-C显示仅PE9306导致更快的线性生长速率。对体重没有显著影响。
制备另外的示例性构建体,其包括经由组织蛋白酶K切割位点接头与ELP 1-120连接的在N末端的CNP53(PE9446;SEQ ID NO:111和112)、经由组织蛋白酶K切割位点接头与ELP 1-120连接的在N末端的CNP22(PE9456;SEQ ID NO:113和114)、经由组织蛋白酶K切割位点接头与ELP1-120连接的在C末端的CNP37(PE9486;SEQ ID NO:115和116)、经由组织蛋白酶K切割位点接头与ELP 1-120连接的在C末端的CNP53(PE9486;SEQ ID NO:117和118)、和经由组织蛋白酶K切割位点接头与ELP1-120连接的在C末端的CNP22(PE9506;SEQ ID NO:119和120)。
实施例4–GLP-2ELP构建体的制备
合成编码GLP-2序列的DNA以掺入A2G突变以增加DPP-IV抗性。将其用限制酶XbaI和BsrGI消化,然后亚克隆到用XbaI和Acc65I切割的质粒pPE0003中,得到质粒pPE0503。该融合将GLP-2序列置于ELP1-120序列的N末端。。
在基于细胞的cAMP效力测定中分析纯化的PE0503蛋白,并显示EC50为1.75nM,而GLP-2肽为0.24nM。
实施例5-体内评价GLP-2ELP构建体
如表5所示,在11天的给药期内,将雄性Sprague Dawley大鼠(200-220g,n=12/组)皮下注射PE0503或GLP-2(A2G)肽。
表5
在第12天处死动物并进行中线切口,取出小肠,拉伸至其最大长度并测量。然后从内腔冲洗粪便物质并记录小肠重量。图4显示,与安慰剂相比,用PE0503治疗导致小肠重量的显著增加,即使只是每四天给药一次(Q4D)。如对GLP-2受体激动剂所预期的,小肠切片的组织学分析表明与载体(盐水)相比绒毛高度明显增加。由于人体的半衰期明显更长,因此数据证实PE0503适合于在人体每周一次或更少的给药。
实施例6–FGF21ELP构建体的制备
合成FGF21基因序列,用限制酶BglI/EcoRI消化,然后亚克隆到质粒pPE0003以提供质粒pPE9183(SEQ ID NO:131和132),将FGF21序列置于ELP 1-120序列的C-端。
合成FGF21基因序列,用限制酶BglI/EcoRI消化,然后亚克隆到质粒pPB1023以提供质粒pPE9193(SEQ ID NO:133和134),将FGF21序列置于ELP 1-120序列的C-端。这产生了双重激动剂,其中GLP-1在ELP聚合物的一端且FGF21在另一端。
引用参考
本发明引用的所有专利和出版物的全部内容通过提述并入本发明,包括以下公开的出版物。
本发明所讨论的出版物仅仅是为了在本发明的提交日之前的公开提供。本发明中的任何内容均不应解释为承认凭借先前的公开,本发明没有资格早于此类出版物。
本发明通过引用完整并入以下出版物用于所有目的:US 2001/0034050 A1;US2009/0220455;US 8,334,257;US 2013/0310538;US 2013/0172274;US 2011/0236384;US6,582,926;US 7,429,458;US 7,364,859;US 8,178,495;US 2013/0079277;US 2013/0085099;US 2013/0143802;US 2014/0024600;US 2011/0178017;US 7,709,227;US 2011/0123487;US 8,729,018;US 2014/0171370;US 2013/0150291;WO/2014/113434;US 2014/0213516,PCT/US2015/061955;和美国临时申请号62/113,943、62/145,770和62/150,679。
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序列表
<110> 费斯生物制药公司
Jowett, James
Ballance, David James
<120> 用于受控和持续释放的ELP融合蛋白
<130> PHAS-033/02WO 309646-2248
<140> PCT申请
<141> 在此递交
<150> US 62/442,057
<151> 2017-01-04
<150> US 62/332,803
<151> 2016-05-06
<160> 134
<170> PatentIn版本3.5
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485 490 495
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545 550 555 560
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35 40 45
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85 90 95
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115 120 125
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130 135 140
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
145 150 155 160
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val
165 170 175
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195 200 205
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210 215 220
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245 250 255
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260 265 270
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275 280 285
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290 295 300
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
305 310 315 320
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
325 330 335
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
340 345 350
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly
355 360 365
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala
370 375 380
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
385 390 395 400
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
405 410 415
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
420 425 430
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly
435 440 445
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala
450 455 460
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
465 470 475 480
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
485 490 495
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
500 505 510
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
515 520 525
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala
530 535 540
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
545 550 555 560
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
565 570 575
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
580 585 590
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
595 600 605
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala
610 615 620
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
625 630 635 640
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val
645 650 655
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
660 665 670
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
675 680 685
Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val
690 695 700
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
705 710 715 720
Val Pro Gly Ala Gly Val Pro Gly Val Gly
725 730
<210> 17
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> 人重组毒晰外泌肽-4
<400> 17
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 18
<211> 31
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-31)
<400> 18
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro
20 25 30
<210> 19
<211> 30
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-30)
<400> 19
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly
20 25 30
<210> 20
<211> 32
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-32)
<400> 20
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
<210> 21
<211> 33
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-33)
<400> 21
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser
<210> 22
<211> 34
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-34)
<400> 22
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly
<210> 23
<211> 35
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-35)
<400> 23
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala
35
<210> 24
<211> 36
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-36)
<400> 24
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro
35
<210> 25
<211> 37
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-37)
<400> 25
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro
35
<210> 26
<211> 38
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (1-38)
<400> 26
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro
35
<210> 27
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 人重组毒晰外泌肽-4 (9-39)
<400> 27
Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu
1 5 10 15
Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30
<210> 28
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人重组毒晰外泌肽-4 (9-31)
<400> 28
Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu
1 5 10 15
Trp Leu Lys Asn Gly Gly Pro
20
<210> 29
<211> 46
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4-具有N端Tev切割位点的ELP序列
<400> 29
Met Glu Asn Leu Tyr Phe Gln His Gly Glu Gly Thr Phe Thr Ser Asp
1 5 10 15
Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp
20 25 30
Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
35 40 45
<210> 30
<211> 58
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4-具有DsbA前导序列的ELP序列
<400> 30
Met Lys Lys Ile Trp Leu Ala Leu Ala Gly Leu Val Leu Ala Phe Ser
1 5 10 15
Ala Ser Ala His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln
20 25 30
Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly
35 40 45
Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
50 55
<210> 31
<211> 31
<212> PRT
<213> 未知
<220>
<223> GLP-1 (A8G 7-37)
<400> 31
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210> 32
<211> 30
<212> PRT
<213> 未知
<220>
<223> GLP-1(7-36)
<400> 32
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210> 33
<211> 30
<212> PRT
<213> 未知
<220>
<223> GLP-1(7-36) 2位为G
<400> 33
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210> 34
<211> 38
<212> PRT
<213> 未知
<220>
<223> GLP-1(A8G 1-37)
<400> 34
Met Glu Asn Leu Tyr Phe Gln His Gly Glu Gly Thr Phe Thr Ser Asp
1 5 10 15
Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp
20 25 30
Leu Val Lys Gly Arg Gly
35
<210> 35
<211> 44
<212> PRT
<213> 未知
<220>
<223> GLP-1受体激动剂
<400> 35
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
35 40
<210> 36
<211> 31
<212> PRT
<213> 未知
<220>
<223> GLP-1受体激动剂
<400> 36
His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Ile Lys Gly Arg Gly
20 25 30
<210> 37
<211> 48
<212> PRT
<213> 未知
<220>
<223> GLP-1 A8G
<400> 37
Met Glu Asn Leu Tyr Phe Gln His Gly Glu Gly Thr Phe Thr Ser Asp
1 5 10 15
Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp
20 25 30
Leu Val Lys Gly Arg Gly Leu Glu Gly Met Gly Gly Pro Gly Val Gly
35 40 45
<210> 38
<211> 22
<212> PRT
<213> 未知
<220>
<223> 毒晰外泌肽-4 (9-30)
<400> 38
Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu
1 5 10 15
Trp Leu Lys Asn Gly Gly
20
<210> 39
<211> 36
<212> PRT
<213> 人工序列
<220>
<223> 人重组爱帕琳肽-36
<400> 39
Leu Val Gln Pro Arg Gly Ser Arg Asn Gly Pro Gly Pro Trp Gln Gly
1 5 10 15
Gly Arg Arg Lys Phe Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly
20 25 30
Pro Met Pro Phe
35
<210> 40
<211> 642
<212> PRT
<213> 人工序列
<220>
<223> pPE0518-ELP1-120 爱帕琳肽-36
<400> 40
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Leu Val
595 600 605
Gln Pro Arg Gly Ser Arg Asn Gly Pro Gly Pro Trp Gln Gly Gly Arg
610 615 620
Arg Lys Phe Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly Pro Met
625 630 635 640
Pro Phe
<210> 41
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人重组爱帕琳肽-17
<400> 41
Lys Phe Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro
1 5 10 15
Phe
<210> 42
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人重组Pyr-爱帕琳肽-13
<220>
<221> 其它特征
<222> (1)..()
<223> 可用焦谷氨酸部分修饰
<400> 42
Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe
1 5 10
<210> 43
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人重组爱帕琳肽-13
<400> 43
Gln Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe
1 5 10
<210> 44
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人重组爱帕琳肽-12
<400> 44
Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe
1 5 10
<210> 45
<211> 322
<212> PRT
<213> 人工序列
<220>
<223> 人重组精氨酸酶
<400> 45
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys
<210> 46
<211> 927
<212> PRT
<213> 人工序列
<220>
<223> pPE0140-精氨酸酶 ELP1-120
<400> 46
Met Ser Ala Lys Ser Arg Thr Ile Gly Ile Ile Gly Ala Pro Phe Ser
1 5 10 15
Lys Gly Gln Pro Arg Gly Gly Val Glu Glu Gly Pro Thr Val Leu Arg
20 25 30
Lys Ala Gly Leu Leu Glu Lys Leu Lys Glu Gln Glu Cys Asp Val Lys
35 40 45
Asp Tyr Gly Asp Leu Pro Phe Ala Asp Ile Pro Asn Asp Ser Pro Phe
50 55 60
Gln Ile Val Lys Asn Pro Arg Ser Val Gly Lys Ala Ser Glu Gln Leu
65 70 75 80
Ala Gly Lys Val Ala Glu Val Lys Lys Asn Gly Arg Ile Ser Leu Val
85 90 95
Leu Gly Gly Asp His Ser Leu Ala Ile Gly Ser Ile Ser Gly His Ala
100 105 110
Arg Val His Pro Asp Leu Gly Val Ile Trp Val Asp Ala His Thr Asp
115 120 125
Ile Asn Thr Pro Leu Thr Thr Thr Ser Gly Asn Leu His Gly Gln Pro
130 135 140
Val Ser Phe Leu Leu Lys Glu Leu Lys Gly Lys Ile Pro Asp Val Pro
145 150 155 160
Gly Phe Ser Trp Val Thr Pro Cys Ile Ser Ala Lys Asp Ile Val Tyr
165 170 175
Ile Gly Leu Arg Asp Val Asp Pro Gly Glu His Tyr Ile Leu Lys Thr
180 185 190
Leu Gly Ile Lys Tyr Phe Ser Met Thr Glu Val Asp Arg Leu Gly Ile
195 200 205
Gly Lys Val Met Glu Glu Thr Leu Ser Tyr Leu Leu Gly Arg Lys Lys
210 215 220
Arg Pro Ile His Leu Ser Phe Asp Val Asp Gly Leu Asp Pro Ser Phe
225 230 235 240
Thr Pro Ala Thr Gly Thr Pro Val Val Gly Gly Leu Thr Tyr Arg Glu
245 250 255
Gly Leu Tyr Ile Thr Glu Glu Ile Tyr Lys Thr Gly Leu Leu Ser Gly
260 265 270
Leu Asp Ile Met Glu Val Asn Pro Ser Leu Gly Lys Thr Pro Glu Glu
275 280 285
Val Thr Arg Thr Val Asn Thr Ala Val Ala Ile Thr Leu Ala Cys Phe
290 295 300
Gly Leu Ala Arg Glu Gly Asn His Lys Pro Ile Asp Tyr Leu Asn Pro
305 310 315 320
Pro Lys Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
325 330 335
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
340 345 350
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
355 360 365
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
370 375 380
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
385 390 395 400
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
405 410 415
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
420 425 430
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
435 440 445
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
450 455 460
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
465 470 475 480
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
485 490 495
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
500 505 510
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
515 520 525
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
530 535 540
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
545 550 555 560
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
565 570 575
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
580 585 590
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
595 600 605
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
610 615 620
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
625 630 635 640
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
645 650 655
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
660 665 670
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
675 680 685
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
690 695 700
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
705 710 715 720
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
725 730 735
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
740 745 750
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
755 760 765
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
770 775 780
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
785 790 795 800
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
805 810 815
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
820 825 830
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
835 840 845
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
850 855 860
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
865 870 875 880
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
885 890 895
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
900 905 910
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro
915 920 925
<210> 47
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人重组CNP22
<400> 47
Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser
1 5 10 15
Met Ser Gly Leu Gly Cys
20
<210> 48
<211> 628
<212> PRT
<213> 人工序列
<220>
<223> ELP1-120 CNP22 融合
<400> 48
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Gly Gly Leu
595 600 605
Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met Ser
610 615 620
Gly Leu Gly Cys
625
<210> 49
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> 人重组CNP37
<400> 49
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys
35
<210> 50
<211> 643
<212> PRT
<213> 人工序列
<220>
<223> pPE0493-ELP1-120 CNP37
<400> 50
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Gly Gln Glu
595 600 605
His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly Leu Ser
610 615 620
Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met Ser Gly
625 630 635 640
Leu Gly Cys
<210> 51
<211> 53
<212> PRT
<213> 人工序列
<220>
<223> 人重组CNP-53
<400> 51
Asp Leu Arg Val Asp Thr Lys Ser Arg Ala Ala Trp Ala Arg Leu Leu
1 5 10 15
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
20 25 30
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
35 40 45
Ser Gly Leu Gly Cys
50
<210> 52
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> 人重组CNP-39
<400> 52
Pro Gly Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys
1 5 10 15
Lys Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly
20 25 30
Ser Met Ser Gly Leu Gly Cys
35
<210> 53
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-1
<400> 53
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210> 54
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-1 (9-31)
<400> 54
Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala
1 5 10 15
Trp Leu Val Lys Gly Arg
20
<210> 55
<211> 633
<212> PRT
<213> 人工序列
<220>
<223> CNP22 GGS2X ELP1-120 融合
<400> 55
Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser
1 5 10 15
Met Ser Gly Leu Gly Cys Gly Gly Ser Gly Gly Ser Val Pro Gly Val
20 25 30
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
35 40 45
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
50 55 60
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
65 70 75 80
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
85 90 95
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
100 105 110
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
115 120 125
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
130 135 140
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
145 150 155 160
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
165 170 175
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
180 185 190
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
195 200 205
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
210 215 220
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
225 230 235 240
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
245 250 255
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
260 265 270
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
275 280 285
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
290 295 300
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
305 310 315 320
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
325 330 335
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
355 360 365
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
370 375 380
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
385 390 395 400
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
405 410 415
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
420 425 430
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
435 440 445
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
450 455 460
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
465 470 475 480
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
485 490 495
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
500 505 510
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
515 520 525
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
530 535 540
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
545 550 555 560
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
565 570 575
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
580 585 590
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
595 600 605
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
610 615 620
Pro Gly Gly Gly Val Pro Gly Trp Pro
625 630
<210> 56
<211> 732
<212> PRT
<213> 人工序列
<220>
<223> ELP1-120 pro-CNP
<400> 56
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Met His
595 600 605
Leu Ser Gln Leu Leu Ala Cys Ala Leu Leu Leu Thr Leu Leu Ser Leu
610 615 620
Arg Pro Ser Glu Ala Lys Pro Gly Ala Pro Pro Lys Val Pro Arg Thr
625 630 635 640
Pro Pro Ala Glu Glu Leu Ala Glu Pro Gln Ala Ala Gly Gly Gly Gln
645 650 655
Lys Lys Gly Asp Lys Ala Pro Gly Gly Gly Gly Ala Asn Leu Lys Gly
660 665 670
Asp Arg Ser Arg Leu Leu Arg Asp Leu Arg Val Asp Thr Lys Ser Arg
675 680 685
Ala Ala Trp Ala Arg Leu Leu Gln Glu His Pro Asn Ala Arg Lys Tyr
690 695 700
Lys Gly Ala Asn Lys Lys Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys
705 710 715 720
Leu Asp Arg Ile Gly Ser Met Ser Gly Leu Gly Cys
725 730
<210> 57
<211> 643
<212> PRT
<213> 人工序列
<220>
<223> CNP37 ELP1-120 融合
<400> 57
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
35 40 45
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
50 55 60
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
65 70 75 80
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
85 90 95
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
115 120 125
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
130 135 140
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
145 150 155 160
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
165 170 175
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
180 185 190
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
195 200 205
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
210 215 220
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
225 230 235 240
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
245 250 255
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
260 265 270
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
275 280 285
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
290 295 300
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
325 330 335
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
340 345 350
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
370 375 380
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
385 390 395 400
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
405 410 415
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
420 425 430
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
435 440 445
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
450 455 460
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
465 470 475 480
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
485 490 495
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
500 505 510
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
515 520 525
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
530 535 540
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
545 550 555 560
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
565 570 575
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
580 585 590
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
595 600 605
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
610 615 620
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
625 630 635 640
Gly Trp Pro
<210> 58
<211> 628
<212> PRT
<213> 人工序列
<220>
<223> pPE0497-毒晰外泌肽-4 (9-31)-ELP1-120
<400> 58
Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu
1 5 10 15
Trp Leu Lys Asn Gly Gly Pro Val Pro Gly Val Gly Val Pro Gly Val
20 25 30
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
35 40 45
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
50 55 60
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
65 70 75 80
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
85 90 95
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
100 105 110
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
115 120 125
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
130 135 140
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
145 150 155 160
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
165 170 175
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
180 185 190
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
195 200 205
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
210 215 220
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
225 230 235 240
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
245 250 255
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
260 265 270
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
275 280 285
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
290 295 300
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
305 310 315 320
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
325 330 335
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
355 360 365
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
370 375 380
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
385 390 395 400
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
405 410 415
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
420 425 430
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
435 440 445
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
450 455 460
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
465 470 475 480
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
485 490 495
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
500 505 510
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
515 520 525
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
530 535 540
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
545 550 555 560
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
565 570 575
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
580 585 590
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
595 600 605
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
610 615 620
Pro Gly Trp Pro
625
<210> 59
<211> 636
<212> PRT
<213> 人工序列
<220>
<223> pPE0496-毒晰外泌肽-4 (9-39) ELP1-120
<400> 59
Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu
1 5 10 15
Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Val
20 25 30
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
35 40 45
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
85 90 95
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
115 120 125
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
130 135 140
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
165 170 175
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
180 185 190
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
210 215 220
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
225 230 235 240
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
260 265 270
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
305 310 315 320
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
355 360 365
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
405 410 415
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
435 440 445
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
485 490 495
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
515 520 525
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
530 535 540
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
565 570 575
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
580 585 590
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
595 600 605
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
610 615 620
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro
625 630 635
<210> 60
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人重组毒晰外泌肽-4 (9-30)
<400> 60
Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu
1 5 10 15
Trp Leu Lys Asn Gly Gly
20
<210> 61
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 人重组M-毒晰外泌肽-4 (9-31)
<400> 61
Met Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile
1 5 10 15
Glu Trp Leu Lys Asn Gly Gly Pro
20
<210> 62
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 人重组M-毒晰外泌肽-4 (9-39)
<400> 62
Met Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile
1 5 10 15
Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30
<210> 63
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人重组M-毒晰外泌肽-4 (9-30)
<400> 63
Met Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile
1 5 10 15
Glu Trp Leu Lys Asn Gly Gly
20
<210> 64
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-1 (9-29)
<400> 64
Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala
1 5 10 15
Trp Leu Val Lys Gly
20
<210> 65
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-1-毒晰外泌肽-4
<400> 65
Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala
1 5 10 15
Trp Leu Val Lys Gly Arg Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30
<210> 66
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 人重组Jant-4 (9-30)
<400> 66
Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Val Arg Glu Phe Ile Ala
1 5 10 15
Trp Leu Val Lys Gly Arg
20
<210> 67
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 人重组Jant-4 (9-39)
<400> 67
Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Val Arg Glu Phe Ile Ala
1 5 10 15
Trp Leu Val Lys Gly Arg Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30
<210> 68
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-2
<400> 68
His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 69
<211> 638
<212> PRT
<213> 人工序列
<220>
<223> pPE0527-GLP-2-ELP1-120
<400> 69
His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
35 40 45
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
50 55 60
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
65 70 75 80
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
85 90 95
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
115 120 125
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
130 135 140
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
145 150 155 160
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
165 170 175
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
180 185 190
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
195 200 205
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
210 215 220
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
225 230 235 240
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
245 250 255
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
260 265 270
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
275 280 285
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
290 295 300
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
325 330 335
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
340 345 350
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
370 375 380
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
385 390 395 400
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
405 410 415
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
420 425 430
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
435 440 445
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
450 455 460
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
465 470 475 480
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
485 490 495
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
500 505 510
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
515 520 525
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
530 535 540
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
545 550 555 560
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
565 570 575
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
580 585 590
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
595 600 605
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
610 615 620
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro
625 630 635
<210> 70
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-2(A2G)
<400> 70
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 71
<211> 638
<212> PRT
<213> 人工序列
<220>
<223> pPE0503-GLP-2(A2G)-ELP1-120
<400> 71
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
35 40 45
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
50 55 60
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
65 70 75 80
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
85 90 95
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
115 120 125
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
130 135 140
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
145 150 155 160
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
165 170 175
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
180 185 190
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
195 200 205
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
210 215 220
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
225 230 235 240
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
245 250 255
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
260 265 270
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
275 280 285
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
290 295 300
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
325 330 335
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
340 345 350
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
370 375 380
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
385 390 395 400
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
405 410 415
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
420 425 430
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
435 440 445
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
450 455 460
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
465 470 475 480
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
485 490 495
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
500 505 510
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
515 520 525
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
530 535 540
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
545 550 555 560
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
565 570 575
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
580 585 590
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
595 600 605
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
610 615 620
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro
625 630 635
<210> 72
<211> 39
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-2(A2G)-(GGS)2x 接头
<400> 72
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Ser Gly Gly Ser
35
<210> 73
<211> 644
<212> PRT
<213> 人工序列
<220>
<223> pPE0526 GLP-2(A2G)-(GGS)2x 接头 ELP1-120
<400> 73
His Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp Gly Gly Ser Gly Gly Ser Val Pro Gly Val Gly Val Pro Gly Val
35 40 45
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
50 55 60
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
65 70 75 80
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
85 90 95
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
100 105 110
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
115 120 125
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
130 135 140
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
145 150 155 160
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
165 170 175
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
180 185 190
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
195 200 205
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
210 215 220
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
225 230 235 240
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
245 250 255
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
260 265 270
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
275 280 285
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
290 295 300
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
305 310 315 320
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
325 330 335
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
340 345 350
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
355 360 365
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
370 375 380
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
385 390 395 400
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
405 410 415
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
420 425 430
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
435 440 445
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
450 455 460
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
465 470 475 480
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
485 490 495
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
500 505 510
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
515 520 525
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
530 535 540
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
545 550 555 560
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
565 570 575
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
580 585 590
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
595 600 605
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
610 615 620
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
625 630 635 640
Pro Gly Trp Pro
<210> 74
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人重组GLP-2-共有
<220>
<221> 其它特征
<222> (2)..(2)
<223> Xaa可为Ala, Gly, Leu, Ile或Val
<400> 74
His Xaa Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210> 75
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人重组铁调素
<400> 75
Asp Thr His Phe Pro Ile Cys Ile Phe Cys Cys Gly Cys Cys His Arg
1 5 10 15
Ser Lys Cys Gly Met Cys Cys Lys Thr
20 25
<210> 76
<211> 631
<212> PRT
<213> 人工序列
<220>
<223> pPE0479 ELP1-120 铁调素
<400> 76
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Trp Val Gly Asp Thr
595 600 605
His Phe Pro Ile Cys Ile Phe Cys Cys Gly Cys Cys His Arg Ser Lys
610 615 620
Cys Gly Met Cys Cys Lys Thr
625 630
<210> 77
<211> 630
<212> PRT
<213> 人工序列
<220>
<223> pPE0487 铁调素 ELP1-120
<400> 77
Asp Thr His Phe Pro Ile Cys Ile Phe Cys Cys Gly Cys Cys His Arg
1 5 10 15
Ser Lys Cys Gly Met Cys Cys Lys Thr Val Pro Gly Val Gly Val Pro
20 25 30
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
35 40 45
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
50 55 60
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
65 70 75 80
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
85 90 95
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
100 105 110
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
115 120 125
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
130 135 140
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
145 150 155 160
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
165 170 175
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
180 185 190
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
195 200 205
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
210 215 220
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
225 230 235 240
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
245 250 255
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
260 265 270
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
275 280 285
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
290 295 300
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
305 310 315 320
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
325 330 335
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
340 345 350
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
355 360 365
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
370 375 380
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
385 390 395 400
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
405 410 415
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
420 425 430
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
435 440 445
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
450 455 460
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
465 470 475 480
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
485 490 495
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
500 505 510
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
515 520 525
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
530 535 540
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
545 550 555 560
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
565 570 575
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
580 585 590
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
595 600 605
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
610 615 620
Gly Val Pro Gly Trp Pro
625 630
<210> 78
<211> 70
<212> PRT
<213> 人工序列
<220>
<223> 人重组IGF-1
<400> 78
Gly Pro Glu Thr Leu Cys Gly Ala Glu Leu Val Asp Ala Leu Gln Phe
1 5 10 15
Val Cys Gly Asp Arg Gly Phe Tyr Phe Asn Lys Pro Thr Gly Tyr Gly
20 25 30
Ser Ser Ser Arg Arg Ala Pro Gln Thr Gly Ile Val Asp Glu Cys Cys
35 40 45
Phe Arg Ser Cys Asp Leu Arg Arg Leu Glu Met Tyr Cys Ala Pro Leu
50 55 60
Lys Pro Ala Lys Ser Ala
65 70
<210> 79
<211> 675
<212> PRT
<213> 人工序列
<220>
<223> pPE0410 IGF-1 ELP1-120
<400> 79
Gly Pro Glu Thr Leu Cys Gly Ala Glu Leu Val Asp Ala Leu Gln Phe
1 5 10 15
Val Cys Gly Asp Arg Gly Phe Tyr Phe Asn Lys Pro Thr Gly Tyr Gly
20 25 30
Ser Ser Ser Arg Arg Ala Pro Gln Thr Gly Ile Val Asp Glu Cys Cys
35 40 45
Phe Arg Ser Cys Asp Leu Arg Arg Leu Glu Met Tyr Cys Ala Pro Leu
50 55 60
Lys Pro Ala Lys Ser Ala Val Pro Gly Val Gly Val Pro Gly Val Gly
65 70 75 80
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
85 90 95
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
100 105 110
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
115 120 125
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
130 135 140
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
145 150 155 160
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
165 170 175
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
180 185 190
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
195 200 205
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
210 215 220
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
225 230 235 240
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
245 250 255
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
260 265 270
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
275 280 285
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
290 295 300
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
305 310 315 320
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
325 330 335
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
340 345 350
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
355 360 365
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
370 375 380
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
385 390 395 400
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
405 410 415
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
420 425 430
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
435 440 445
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
450 455 460
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
465 470 475 480
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
485 490 495
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
500 505 510
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
515 520 525
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
530 535 540
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
545 550 555 560
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
565 570 575
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
580 585 590
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
595 600 605
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
610 615 620
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
625 630 635 640
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
645 650 655
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
660 665 670
Gly Trp Pro
675
<210> 80
<211> 800
<212> PRT
<213> 人工序列
<220>
<223> pPE0413 IGF-1 ELPbetav2 144聚体
<400> 80
Gly Pro Glu Thr Leu Cys Gly Ala Glu Leu Val Asp Ala Leu Gln Phe
1 5 10 15
Val Cys Gly Asp Arg Gly Phe Tyr Phe Asn Lys Pro Thr Gly Tyr Gly
20 25 30
Ser Ser Ser Arg Arg Ala Pro Gln Thr Gly Ile Val Asp Glu Cys Cys
35 40 45
Phe Arg Ser Cys Asp Leu Arg Arg Leu Glu Met Tyr Cys Ala Pro Leu
50 55 60
Lys Pro Ala Lys Ser Ala Val Pro Gly Val Gly Val Pro Gly Val Gly
65 70 75 80
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val
85 90 95
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
100 105 110
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
115 120 125
Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val
130 135 140
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
145 150 155 160
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val
165 170 175
Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
180 185 190
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
195 200 205
Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val
210 215 220
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
225 230 235 240
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val
245 250 255
Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
260 265 270
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
275 280 285
Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val
290 295 300
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
305 310 315 320
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val
325 330 335
Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
340 345 350
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly
355 360 365
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val
370 375 380
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
385 390 395 400
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
405 410 415
Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
420 425 430
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly
435 440 445
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
450 455 460
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
465 470 475 480
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
485 490 495
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
500 505 510
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly
515 520 525
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala
530 535 540
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
545 550 555 560
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
565 570 575
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
580 585 590
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly
595 600 605
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala
610 615 620
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
625 630 635 640
Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
645 650 655
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
660 665 670
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
675 680 685
Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala
690 695 700
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
705 710 715 720
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
725 730 735
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro
740 745 750
Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
755 760 765
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala
770 775 780
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Val Pro Gly Trp Pro
785 790 795 800
<210> 81
<211> 1935
<212> DNA
<213> 人工序列
<220>
<223> ELP1-120 CNP37 融合
<400> 81
atggtaccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 60
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 120
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 180
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 240
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 300
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 360
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 420
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 480
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 540
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 600
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 660
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 720
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 780
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 840
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 900
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 960
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1020
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1080
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1140
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1200
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1260
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1320
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1380
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1440
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1500
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1560
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1620
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1680
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1740
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1800
ggtgtgccgg gcgtggggca ggaacatccg aacgcgcgta aatataaagg tgcgaacaaa 1860
aaaggcctga gcaaaggctg ctttggcctg aaactggatc gcattggcag catgagcggc 1920
ctgggctgct gataa 1935
<210> 82
<211> 1935
<212> DNA
<213> 人工序列
<220>
<223> CNP37 ELP1-120 融合
<400> 82
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg cggtgtaccg 120
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 180
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 240
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 300
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 360
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 420
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 480
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 540
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 600
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 660
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 720
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 780
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 840
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 900
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 960
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1020
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1080
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1140
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1200
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1260
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1320
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1380
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1440
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1500
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1560
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1620
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1680
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1740
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1800
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1860
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1920
ggctggccgt gataa 1935
<210> 83
<211> 648
<212> PRT
<213> 人工序列
<220>
<223> CNP37 GGS2x ELP1-120 融合
<400> 83
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Gly Gly Ser Gly Gly Ser Val Pro Gly Val Gly
35 40 45
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
50 55 60
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
65 70 75 80
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
85 90 95
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
115 120 125
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
130 135 140
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
145 150 155 160
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
165 170 175
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
180 185 190
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
195 200 205
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
210 215 220
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
225 230 235 240
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
245 250 255
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
260 265 270
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
275 280 285
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
290 295 300
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
325 330 335
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
370 375 380
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
385 390 395 400
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
405 410 415
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
420 425 430
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
435 440 445
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
450 455 460
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
465 470 475 480
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
485 490 495
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
500 505 510
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
515 520 525
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
530 535 540
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
545 550 555 560
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
565 570 575
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
580 585 590
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
595 600 605
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
610 615 620
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
625 630 635 640
Gly Gly Gly Val Pro Gly Trp Pro
645
<210> 84
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 人重组尿扩张素
<400> 84
Thr Ala Pro Arg Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
1 5 10 15
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
20 25 30
<210> 85
<211> 637
<212> PRT
<213> 人工序列
<220>
<223> pPE0483 尿扩张素 ELP1-120
<400> 85
Thr Ala Pro Arg Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
1 5 10 15
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
20 25 30
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
35 40 45
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
50 55 60
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
65 70 75 80
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
85 90 95
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
100 105 110
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
115 120 125
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
130 135 140
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
145 150 155 160
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
165 170 175
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
180 185 190
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
195 200 205
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
210 215 220
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
225 230 235 240
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
245 250 255
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
260 265 270
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
275 280 285
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
290 295 300
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
305 310 315 320
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
325 330 335
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
340 345 350
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
355 360 365
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
370 375 380
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
385 390 395 400
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
405 410 415
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
420 425 430
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
435 440 445
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
450 455 460
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
465 470 475 480
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
485 490 495
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
500 505 510
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
515 520 525
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
530 535 540
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
545 550 555 560
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
565 570 575
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
580 585 590
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
595 600 605
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
610 615 620
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro
625 630 635
<210> 86
<211> 638
<212> PRT
<213> 人工序列
<220>
<223> pPE0484 ELP1-120 尿扩张素
<400> 86
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Gly Thr Ala
595 600 605
Pro Arg Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg
610 615 620
Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
625 630 635
<210> 87
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> GGS 三肽
<400> 87
Gly Gly Ser
1
<210> 88
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 铁调素 (1-9)
<400> 88
Asp Thr His Phe Pro Ile Cys Ile Phe
1 5
<210> 89
<211> 43
<212> PRT
<213> 人工序列
<220>
<223> 胸腺素 beta 4
<400> 89
Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lys Ser Lys
1 5 10 15
Leu Lys Lys Thr Glu Thr Gln Glu Lys Asn Pro Leu Pro Ser Lys Glu
20 25 30
Thr Ile Glu Gln Glu Lys Gln Ala Gly Glu Ser
35 40
<210> 90
<211> 648
<212> PRT
<213> 人工序列
<220>
<223> pPE0320 胸腺素 beta 4 ELP1-120
<400> 90
Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lys Ser Lys
1 5 10 15
Leu Lys Lys Thr Glu Thr Gln Glu Lys Asn Pro Leu Pro Ser Lys Glu
20 25 30
Thr Ile Glu Gln Glu Lys Gln Ala Gly Glu Ser Val Pro Gly Val Gly
35 40 45
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
50 55 60
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
65 70 75 80
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
85 90 95
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
115 120 125
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
130 135 140
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
145 150 155 160
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
165 170 175
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
180 185 190
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
195 200 205
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
210 215 220
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
225 230 235 240
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
245 250 255
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
260 265 270
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
275 280 285
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
290 295 300
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
325 330 335
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
370 375 380
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
385 390 395 400
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
405 410 415
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
420 425 430
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
435 440 445
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
450 455 460
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
465 470 475 480
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
485 490 495
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
500 505 510
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
515 520 525
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
530 535 540
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
545 550 555 560
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
565 570 575
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
580 585 590
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
595 600 605
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
610 615 620
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
625 630 635 640
Gly Gly Gly Val Pro Gly Trp Pro
645
<210> 91
<211> 168
<212> PRT
<213> 人工序列
<220>
<223> TRAIL
<400> 91
Val Arg Glu Arg Gly Pro Gln Arg Val Ala Ala His Ile Thr Gly Thr
1 5 10 15
Arg Gly Arg Ser Asn Thr Leu Ser Ser Pro Asn Ser Lys Asn Glu Lys
20 25 30
Ala Leu Gly Arg Lys Ile Asn Ser Trp Glu Ser Ser Arg Ser Gly His
35 40 45
Ser Phe Leu Ser Asn Leu His Leu Arg Asn Gly Glu Leu Val Ile His
50 55 60
Glu Lys Gly Phe Tyr Tyr Ile Tyr Ser Gln Thr Tyr Phe Arg Phe Gln
65 70 75 80
Glu Glu Ile Lys Glu Asn Thr Lys Asn Asp Lys Gln Met Val Gln Tyr
85 90 95
Ile Tyr Lys Tyr Thr Ser Tyr Pro Asp Pro Ile Leu Leu Met Lys Ser
100 105 110
Ala Arg Asn Ser Cys Trp Ser Lys Asp Ala Glu Tyr Gly Leu Tyr Ser
115 120 125
Ile Tyr Gln Gly Gly Ile Phe Glu Leu Lys Glu Asn Asp Arg Ile Phe
130 135 140
Val Ser Val Thr Asn Glu His Leu Ile Asp Met Asp His Glu Ala Ser
145 150 155 160
Phe Phe Gly Ala Phe Leu Val Gly
165
<210> 92
<211> 777
<212> PRT
<213> 人工序列
<220>
<223> pPE0141 ELP1-120 TRAIL
<400> 92
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Pro Gly Gly
595 600 605
Gly Val Arg Glu Arg Gly Pro Gln Arg Val Ala Ala His Ile Thr Gly
610 615 620
Thr Arg Gly Arg Ser Asn Thr Leu Ser Ser Pro Asn Ser Lys Asn Glu
625 630 635 640
Lys Ala Leu Gly Arg Lys Ile Asn Ser Trp Glu Ser Ser Arg Ser Gly
645 650 655
His Ser Phe Leu Ser Asn Leu His Leu Arg Asn Gly Glu Leu Val Ile
660 665 670
His Glu Lys Gly Phe Tyr Tyr Ile Tyr Ser Gln Thr Tyr Phe Arg Phe
675 680 685
Gln Glu Glu Ile Lys Glu Asn Thr Lys Asn Asp Lys Gln Met Val Gln
690 695 700
Tyr Ile Tyr Lys Tyr Thr Ser Tyr Pro Asp Pro Ile Leu Leu Met Lys
705 710 715 720
Ser Ala Arg Asn Ser Cys Trp Ser Lys Asp Ala Glu Tyr Gly Leu Tyr
725 730 735
Ser Ile Tyr Gln Gly Gly Ile Phe Glu Leu Lys Glu Asn Asp Arg Ile
740 745 750
Phe Val Ser Val Thr Asn Glu His Leu Ile Asp Met Asp His Glu Ala
755 760 765
Ser Phe Phe Gly Ala Phe Leu Val Gly
770 775
<210> 93
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> GGGGS 接头
<400> 93
Gly Gly Gly Gly Ser
1 5
<210> 94
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> PAPAP 接头
<400> 94
Pro Ala Pro Ala Pro
1 5
<210> 95
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> EAAAK 接头
<400> 95
Glu Ala Ala Ala Lys
1 5
<210> 96
<211> 1950
<212> DNA
<213> 人工序列
<220>
<223> CNP37 GGS2x ELP1-120 融合
<400> 96
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg cggtggctct 120
ggcggttctg taccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 180
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 240
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 300
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 360
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 420
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 480
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 540
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 600
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 660
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 720
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 780
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 840
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 900
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 960
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1020
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1080
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1140
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1200
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1260
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1320
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1380
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1440
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1500
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1560
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1620
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1680
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1740
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1800
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1860
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1920
ggtggcggtg tgccgggctg gccgtgataa 1950
<210> 97
<211> 1890
<212> DNA
<213> 人工序列
<220>
<223> ELP1-120 CNP22 融合
<400> 97
atggtaccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 60
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 120
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 180
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 240
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 300
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 360
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 420
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 480
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 540
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 600
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 660
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 720
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 780
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 840
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 900
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 960
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1020
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1080
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1140
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1200
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1260
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1320
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1380
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1440
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1500
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1560
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1620
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1680
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1740
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1800
ggtgtgccgg gctggccggg cctgagcaaa ggctgctttg gcctgaaact ggatcgcatt 1860
ggcagcatga gcggcctggg ctgctgataa 1890
<210> 98
<211> 628
<212> PRT
<213> 人工序列
<220>
<223> CNP22 ELP1-120 融合
<400> 98
Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser
1 5 10 15
Met Ser Gly Leu Gly Cys Gly Val Pro Gly Val Gly Val Pro Gly Val
20 25 30
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
35 40 45
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
50 55 60
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
65 70 75 80
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
85 90 95
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
100 105 110
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
115 120 125
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
130 135 140
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
145 150 155 160
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
165 170 175
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
180 185 190
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
195 200 205
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
210 215 220
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
225 230 235 240
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
245 250 255
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
260 265 270
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
275 280 285
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
290 295 300
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
305 310 315 320
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
325 330 335
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
355 360 365
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
370 375 380
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
385 390 395 400
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
405 410 415
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
420 425 430
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
435 440 445
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
450 455 460
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
465 470 475 480
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
485 490 495
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
500 505 510
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
515 520 525
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
530 535 540
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
545 550 555 560
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
565 570 575
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
580 585 590
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
595 600 605
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
610 615 620
Pro Gly Trp Pro
625
<210> 99
<211> 1890
<212> DNA
<213> 人工序列
<220>
<223> CNP ELP1-120 融合
<400> 99
ggcctgagca aaggctgctt tggcctgaaa ctggatcgca ttggcagcat gagcggcctg 60
ggctgcggtg taccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 120
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 180
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 240
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 300
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 360
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 420
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 480
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 540
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 600
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 660
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 720
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 780
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 840
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 900
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 960
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1020
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1080
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1140
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1200
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1260
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1320
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1380
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1440
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1500
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1560
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1620
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1680
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1740
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1800
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1860
ggtggcggtg tgccgggctg gccgtgataa 1890
<210> 100
<211> 1905
<212> DNA
<213> 人工序列
<220>
<223> CNP22 GGS2X ELP1-120 融合
<400> 100
ggcctgagca aaggctgctt tggcctgaaa ctggatcgca ttggcagcat gagcggcctg 60
ggctgcggtg gctctggcgg ttctgtaccg ggcgtgggtg ttccgggcgt gggtgttccg 120
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 180
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 240
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 300
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 360
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 420
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 480
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 540
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 600
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 660
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 720
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 780
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 840
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 900
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 960
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1020
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1080
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1140
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1200
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1260
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1320
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1380
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1440
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1500
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1560
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1620
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1680
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1740
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1800
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1860
ggtgcaggcg ttccgggtgg cggtgtgccg ggctggccgt gataa 1905
<210> 101
<211> 1920
<212> DNA
<213> 人工序列
<220>
<223> GLP-2 ELP1-120 融合
<400> 101
cacggcgatg gcagcttttc tgatgaaatg aataccattc tggacaacct ggcagcacgc 60
gactttatta actggctgat tcagacgaaa attactgatg taccgggcgt gggtgttccg 120
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 180
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 240
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 300
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 360
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 420
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 480
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 540
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 600
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 660
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 720
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 780
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 840
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 900
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 960
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1020
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1080
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1140
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1200
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1260
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1320
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1380
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1440
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1500
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1560
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggcgt gggtgttccg 1620
ggcgtgggtg ttccgggtgg cggtgtgccg ggcgcaggtg ttcctggtgt aggtgtgccg 1680
ggtgttggtg tgccgggtgt tggtgtacca ggtggcggtg ttccgggtgc aggcgttccg 1740
ggtggcggtg tgccgggcgt gggtgttccg ggcgtgggtg ttccgggtgg cggtgtgccg 1800
ggcgcaggtg ttcctggtgt aggtgtgccg ggtgttggtg tgccgggtgt tggtgtacca 1860
ggtggcggtg ttccgggtgc aggcgttccg ggtggcggtg tgccgggctg gccgtgataa 1920
<210> 102
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> GGS 2X
<400> 102
Gly Gly Ser Gly Gly Ser
1 5
<210> 103
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> GGS 3X
<400> 103
Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5
<210> 104
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> GGGGS 2X
<400> 104
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 105
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> GGGGS 3X
<400> 105
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 106
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> PAPAP 2X
<400> 106
Pro Ala Pro Ala Pro Pro Ala Pro Ala Pro
1 5 10
<210> 107
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> PAPAP 3X
<400> 107
Pro Ala Pro Ala Pro Pro Ala Pro Ala Pro Pro Ala Pro Ala Pro
1 5 10 15
<210> 108
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> EAAAK 2X
<400> 108
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10
<210> 109
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> EAAAK 3X
<400> 109
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
<210> 110
<211> 209
<212> PRT
<213> 人工
<220>
<223> FGF21
<400> 110
Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser
1 5 10 15
Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro
20 25 30
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
35 40 45
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
50 55 60
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
65 70 75 80
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
85 90 95
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
100 105 110
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
115 120 125
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
130 135 140
His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
145 150 155 160
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu
165 170 175
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
180 185 190
Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
195 200 205
Ser
<210> 111
<211> 663
<212> PRT
<213> 人工
<220>
<223> CNP53 CatK ELP1-120 融合 PE9446
<400> 111
Asp Leu Arg Val Asp Thr Lys Ser Arg Ala Ala Trp Ala Arg Leu Leu
1 5 10 15
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
20 25 30
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
35 40 45
Ser Gly Leu Gly Cys Arg Lys Pro Arg Gly Val Pro Gly Val Gly Val
50 55 60
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
65 70 75 80
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
85 90 95
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
115 120 125
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
130 135 140
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
145 150 155 160
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
165 170 175
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
180 185 190
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
195 200 205
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
210 215 220
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
225 230 235 240
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
245 250 255
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
260 265 270
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
275 280 285
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
290 295 300
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
325 330 335
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
340 345 350
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
370 375 380
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
385 390 395 400
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
405 410 415
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
420 425 430
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
435 440 445
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
450 455 460
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
465 470 475 480
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
485 490 495
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
500 505 510
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
515 520 525
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
530 535 540
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
545 550 555 560
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
565 570 575
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
580 585 590
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
595 600 605
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
610 615 620
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
625 630 635 640
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
645 650 655
Gly Gly Val Pro Gly Trp Pro
660
<210> 112
<211> 1989
<212> DNA
<213> 人工
<220>
<223> CNP53 CatK ELP1-120 融合 PE9446
<400> 112
gatctgcgcg tggataccaa aagccgcgcg gcgtgggcgc gcctgctgca ggaacatccg 60
aacgcgcgca aatataaagg cgcgaacaaa aaaggcctga gcaaaggctg ctttggcctg 120
aaactggatc gcattggcag catgagcggc ctgggctgcc gcaaaccgcg cggtgtaccg 180
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 240
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 300
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 360
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 420
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 480
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 540
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 600
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 660
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 720
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 780
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 840
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 900
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 960
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1020
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1080
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1140
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1200
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1260
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1320
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1380
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1440
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1500
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1560
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1620
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1680
ggcgtgggtg ttccgggcgt gggtgttccg ggtggcggtg tgccgggcgc aggtgttcct 1740
ggtgtaggtg tgccgggtgt tggtgtgccg ggtgttggtg taccaggtgg cggtgttccg 1800
ggtgcaggcg ttccgggtgg cggtgtgccg ggcgtgggtg ttccgggcgt gggtgttccg 1860
ggtggcggtg tgccgggcgc aggtgttcct ggtgtaggtg tgccgggtgt tggtgtgccg 1920
ggtgttggtg taccaggtgg cggtgttccg ggtgcaggcg ttccgggtgg cggtgtgccg 1980
ggctggccg 1989
<210> 113
<211> 632
<212> PRT
<213> 人工
<220>
<223> CNP22 CatK ELP1-120 融合 PE9456
<400> 113
Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser
1 5 10 15
Met Ser Gly Leu Gly Cys Arg Lys Pro Arg Gly Val Pro Gly Val Gly
20 25 30
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
35 40 45
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
50 55 60
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
65 70 75 80
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
85 90 95
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
100 105 110
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
115 120 125
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
130 135 140
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
145 150 155 160
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
165 170 175
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
180 185 190
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
195 200 205
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
210 215 220
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
225 230 235 240
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
245 250 255
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
260 265 270
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
275 280 285
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
290 295 300
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
305 310 315 320
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
325 330 335
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
340 345 350
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
355 360 365
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
370 375 380
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
385 390 395 400
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
405 410 415
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
420 425 430
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
435 440 445
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
450 455 460
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
465 470 475 480
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
485 490 495
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
500 505 510
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
515 520 525
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
530 535 540
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
545 550 555 560
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
565 570 575
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
580 585 590
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
595 600 605
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
610 615 620
Gly Gly Gly Val Pro Gly Trp Pro
625 630
<210> 114
<211> 1896
<212> DNA
<213> 人工
<220>
<223> CNP22 CatK ELP1-120 融合 PE9456
<400> 114
ggcctgagca aaggctgctt tggcctgaaa ctggatcgca ttggcagcat gagcggcctg 60
ggctgccgca aaccgcgcgg tgtaccgggc gtgggtgttc cgggcgtggg tgttccgggt 120
ggcggtgtgc cgggcgcagg tgttcctggt gtaggtgtgc cgggtgttgg tgtgccgggt 180
gttggtgtac caggtggcgg tgttccgggt gcaggcgttc cgggtggcgg tgtgccgggc 240
gtgggtgttc cgggcgtggg tgttccgggt ggcggtgtgc cgggcgcagg tgttcctggt 300
gtaggtgtgc cgggtgttgg tgtgccgggt gttggtgtac caggtggcgg tgttccgggt 360
gcaggcgttc cgggtggcgg tgtgccgggc gtgggtgttc cgggcgtggg tgttccgggt 420
ggcggtgtgc cgggcgcagg tgttcctggt gtaggtgtgc cgggtgttgg tgtgccgggt 480
gttggtgtac caggtggcgg tgttccgggt gcaggcgttc cgggtggcgg tgtgccgggc 540
gtgggtgttc cgggcgtggg tgttccgggt ggcggtgtgc cgggcgcagg tgttcctggt 600
gtaggtgtgc cgggtgttgg tgtgccgggt gttggtgtac caggtggcgg tgttccgggt 660
gcaggcgttc cgggtggcgg tgtgccgggc gtgggtgttc cgggcgtggg tgttccgggt 720
ggcggtgtgc cgggcgcagg tgttcctggt gtaggtgtgc cgggtgttgg tgtgccgggt 780
gttggtgtac caggtggcgg tgttccgggt gcaggcgttc cgggtggcgg tgtgccgggc 840
gtgggtgttc cgggcgtggg tgttccgggt ggcggtgtgc cgggcgcagg tgttcctggt 900
gtaggtgtgc cgggtgttgg tgtgccgggt gttggtgtac caggtggcgg tgttccgggt 960
gcaggcgttc cgggtggcgg tgtgccgggc gtgggtgttc cgggcgtggg tgttccgggt 1020
ggcggtgtgc cgggcgcagg tgttcctggt gtaggtgtgc cgggtgttgg tgtgccgggt 1080
gttggtgtac caggtggcgg tgttccgggt gcaggcgttc cgggtggcgg tgtgccgggc 1140
gtgggtgttc cgggcgtggg tgttccgggt ggcggtgtgc cgggcgcagg tgttcctggt 1200
gtaggtgtgc cgggtgttgg tgtgccgggt gttggtgtac caggtggcgg tgttccgggt 1260
gcaggcgttc cgggtggcgg tgtgccgggc gtgggtgttc cgggcgtggg tgttccgggt 1320
ggcggtgtgc cgggcgcagg tgttcctggt gtaggtgtgc cgggtgttgg tgtgccgggt 1380
gttggtgtac caggtggcgg tgttccgggt gcaggcgttc cgggtggcgg tgtgccgggc 1440
gtgggtgttc cgggcgtggg tgttccgggt ggcggtgtgc cgggcgcagg tgttcctggt 1500
gtaggtgtgc cgggtgttgg tgtgccgggt gttggtgtac caggtggcgg tgttccgggt 1560
gcaggcgttc cgggtggcgg tgtgccgggc gtgggtgttc cgggcgtggg tgttccgggt 1620
ggcggtgtgc cgggcgcagg tgttcctggt gtaggtgtgc cgggtgttgg tgtgccgggt 1680
gttggtgtac caggtggcgg tgttccgggt gcaggcgttc cgggtggcgg tgtgccgggc 1740
gtgggtgttc cgggcgtggg tgttccgggt ggcggtgtgc cgggcgcagg tgttcctggt 1800
gtaggtgtgc cgggtgttgg tgtgccgggt gttggtgtac caggtggcgg tgttccgggt 1860
gcaggcgttc cgggtggcgg tgtgccgggc tggccg 1896
<210> 115
<211> 648
<212> PRT
<213> 人工
<220>
<223> ELP1-120 CatK CNP37 融合 PE9486
<400> 115
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro Arg Lys
595 600 605
Pro Arg Gly Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn
610 615 620
Lys Lys Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile
625 630 635 640
Gly Ser Met Ser Gly Leu Gly Cys
645
<210> 116
<211> 1945
<212> DNA
<213> 人工
<220>
<223> ELP1-120 CatK CNP37 融合 PE9486
<400> 116
atggtaccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 60
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 120
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 180
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 240
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 300
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 360
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 420
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 480
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 540
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 600
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 660
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 720
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 780
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 840
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 900
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 960
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1020
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1080
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1140
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1200
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1260
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1320
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1380
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1440
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1500
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1560
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1620
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1680
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1740
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1800
ggtgtgccgg gctggccgcc gcaaaccgcg cggtcaggaa catccgaacg cgcgtaaata 1860
taaaggtgcg aacaaaaaag gcctgagcaa aggctgcttt ggcctgaaac tggatcgcat 1920
tggcagcatg agcggcctgg gctgc 1945
<210> 117
<211> 664
<212> PRT
<213> 人工
<220> ELP1-120 CatK CNP53 融合 PE9496
<223>
<400> 117
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro Arg Lys
595 600 605
Pro Arg Gly Asp Leu Arg Val Asp Thr Lys Ser Arg Ala Ala Trp Ala
610 615 620
Arg Leu Leu Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn
625 630 635 640
Lys Lys Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile
645 650 655
Gly Ser Met Ser Gly Leu Gly Cys
660
<210> 118
<211> 1993
<212> DNA
<213> 人工
<220>
<223> ELP1-120 CatK CNP53 融合 PE9496
<400> 118
atggtaccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 60
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 120
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 180
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 240
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 300
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 360
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 420
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 480
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 540
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 600
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 660
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 720
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 780
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 840
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 900
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 960
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1020
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1080
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1140
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1200
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1260
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1320
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1380
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1440
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1500
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1560
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1620
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1680
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1740
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1800
ggtgtgccgg gctggccgcc gcaaaccgcg cggtgatctg cgcgtggata ccaaaagccg 1860
cgcggcgtgg gcgcgcctgc tgcaggaaca tccgaacgcg cgcaaatata aaggcgcgaa 1920
caaaaaaggc ctgagcaaag gctgctttgg cctgaaactg gatcgcattg gcagcatgag 1980
cggcctgggc tgc 1993
<210> 19
<211> 633
<212> PRT
<213> 人工
<220>
<223> ELP1-120 CatK CNP22 融合 PE9506
<400> 19
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Trp Pro Arg Lys
595 600 605
Pro Arg Gly Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg
610 615 620
Ile Gly Ser Met Ser Gly Leu Gly Cys
625 630
<210> 120
<211> 1900
<212> DNA
<213> 人工
<220>
<223> ELP1-120 CatK CNP22 融合 PE9506
<400> 120
atggtaccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 60
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 120
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 180
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 240
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 300
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 360
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 420
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 480
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 540
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 600
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 660
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 720
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 780
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 840
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 900
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 960
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1020
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1080
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1140
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1200
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1260
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1320
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1380
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1440
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1500
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1560
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1620
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1680
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1740
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1800
ggtgtgccgg gctggccgcc gcaaaccgcg cggtggcctg agcaaaggct gctttggcct 1860
gaaactggat cgcattggca gcatgagcgg cctgggctgc 1900
<210> 121
<211> 647
<212> PRT
<213> 人工
<220>
<223> CNP37 Fxa ELP1-120 融合 PE9206
<400> 121
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Ile Glu Gly Arg Gly Val Pro Gly Val Gly Val
35 40 45
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
50 55 60
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
65 70 75 80
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
85 90 95
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
100 105 110
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
115 120 125
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
130 135 140
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
145 150 155 160
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
165 170 175
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
180 185 190
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
195 200 205
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
210 215 220
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
225 230 235 240
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
245 250 255
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
260 265 270
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
275 280 285
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
290 295 300
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
305 310 315 320
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
325 330 335
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
340 345 350
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
355 360 365
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
370 375 380
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
385 390 395 400
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
405 410 415
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
420 425 430
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
435 440 445
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
450 455 460
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
465 470 475 480
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
485 490 495
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
500 505 510
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
515 520 525
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
530 535 540
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
545 550 555 560
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
565 570 575
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
580 585 590
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
595 600 605
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
610 615 620
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
625 630 635 640
Gly Gly Val Pro Gly Trp Pro
645
<210> 122
<211> 1941
<212> DNA
<213> 人工
<220>
<223> CNP37 Fxa ELP1-120 融合 PE9206
<400> 122
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg cattgaaggc 120
cgcggtgtac cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 180
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 240
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 300
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 360
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 420
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 480
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 540
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 600
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 660
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 720
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 780
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 840
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 900
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 960
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1020
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1080
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1140
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1200
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1260
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1320
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1380
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1440
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1500
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1560
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1620
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1680
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1740
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1800
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1860
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1920
ggcggtgtgc cgggctggcc g 1941
<210> 123
<211> 649
<212> PRT
<213> 人工
<220>
<223> CNP37 凝血酶 ELP1-120 融合 PE9216
<400> 123
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Leu Val Pro Arg Gly Ser Gly Val Pro Gly Val
35 40 45
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
50 55 60
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
65 70 75 80
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
85 90 95
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
100 105 110
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
115 120 125
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
130 135 140
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
145 150 155 160
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
165 170 175
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
180 185 190
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
195 200 205
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
210 215 220
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
225 230 235 240
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
245 250 255
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
260 265 270
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
275 280 285
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
290 295 300
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
305 310 315 320
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
325 330 335
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
340 345 350
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
355 360 365
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
370 375 380
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
385 390 395 400
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
405 410 415
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
420 425 430
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
435 440 445
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
450 455 460
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
465 470 475 480
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
485 490 495
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
500 505 510
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
515 520 525
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
530 535 540
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
545 550 555 560
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
565 570 575
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
580 585 590
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
595 600 605
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
610 615 620
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
625 630 635 640
Pro Gly Gly Gly Val Pro Gly Trp Pro
645
<210> 124
<211> 1947
<212> DNA
<213> 人工
<220>
<223> CNP37 凝血酶 ELP1-120 融合 PE9216
<400> 124
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg cctggtgccg 120
cgcggcagcg gtgtaccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 180
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 240
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 300
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 360
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 420
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 480
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 540
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 600
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 660
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 720
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 780
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 840
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 900
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 960
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1020
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 1080
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 1140
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 1200
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 1260
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1320
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 1380
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 1440
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 1500
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 1560
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1620
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 1680
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 1740
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 1800
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 1860
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1920
ccgggtggcg gtgtgccggg ctggccg 1947
<210> 125
<211> 647
<212> PRT
<213> 人工
<220>
<223> CNP37 CatK ELP1-120 融合 PE9306
<400> 125
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Arg Lys Pro Arg Gly Val Pro Gly Val Gly Val
35 40 45
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
50 55 60
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
65 70 75 80
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
85 90 95
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
100 105 110
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
115 120 125
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
130 135 140
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
145 150 155 160
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
165 170 175
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
180 185 190
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
195 200 205
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
210 215 220
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
225 230 235 240
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
245 250 255
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
260 265 270
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
275 280 285
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
290 295 300
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
305 310 315 320
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
325 330 335
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
340 345 350
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
355 360 365
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
370 375 380
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
385 390 395 400
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
405 410 415
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
420 425 430
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
435 440 445
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
450 455 460
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
465 470 475 480
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
485 490 495
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
500 505 510
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
515 520 525
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
530 535 540
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
545 550 555 560
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
565 570 575
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
580 585 590
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
595 600 605
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
610 615 620
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
625 630 635 640
Gly Gly Val Pro Gly Trp Pro
645
<210> 126
<211> 1941
<212> DNA
<213> 人工
<220>
<223> CNP37 CatK ELP1-120 融合 PE9306
<400> 126
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg ccgcaaaccg 120
cgcggtgtac cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 180
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 240
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 300
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 360
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 420
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 480
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 540
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 600
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 660
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 720
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 780
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 840
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 900
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 960
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1020
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1080
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1140
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1200
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1260
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1320
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1380
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1440
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1500
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1560
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1620
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1680
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1740
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1800
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1860
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1920
ggcggtgtgc cgggctggcc g 1941
<210> 127
<211> 647
<212> PRT
<213> 人工
<220>
<223> CNP37 CatK ELP1-120 融合 PE9316
<400> 127
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Arg Lys Pro Arg Gly Val Pro Gly Val Gly Val
35 40 45
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
50 55 60
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
65 70 75 80
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
85 90 95
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
100 105 110
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
115 120 125
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
130 135 140
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
145 150 155 160
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
165 170 175
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
180 185 190
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
195 200 205
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
210 215 220
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
225 230 235 240
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
245 250 255
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
260 265 270
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
275 280 285
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
290 295 300
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
305 310 315 320
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
325 330 335
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
340 345 350
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
355 360 365
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
370 375 380
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
385 390 395 400
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
405 410 415
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
420 425 430
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
435 440 445
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
450 455 460
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
465 470 475 480
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
485 490 495
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
500 505 510
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
515 520 525
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
530 535 540
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
545 550 555 560
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
565 570 575
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
580 585 590
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
595 600 605
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
610 615 620
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
625 630 635 640
Gly Gly Val Pro Gly Trp Pro
645
<210> 128
<211> 1941
<212> DNA
<213> 人工
<220>
<223> CNP37 CatK ELP1-120 融合 PE9316
<400> 128
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg ccgcaaaccg 120
cgcggtgtac cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 180
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 240
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 300
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 360
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 420
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 480
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 540
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 600
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 660
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 720
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 780
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 840
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 900
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 960
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1020
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1080
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1140
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1200
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1260
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1320
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1380
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1440
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1500
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1560
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1620
ggcggtgtgc cgggcgtggg tgttccgggc gtgggtgttc cgggtggcgg tgtgccgggc 1680
gcaggtgttc ctggtgtagg tgtgccgggt gttggtgtgc cgggtgttgg tgtaccaggt 1740
ggcggtgttc cgggtgcagg cgttccgggt ggcggtgtgc cgggcgtggg tgttccgggc 1800
gtgggtgttc cgggtggcgg tgtgccgggc gcaggtgttc ctggtgtagg tgtgccgggt 1860
gttggtgtgc cgggtgttgg tgtaccaggt ggcggtgttc cgggtgcagg cgttccgggt 1920
ggcggtgtgc cgggctggcc g 1941
<210> 129
<211> 649
<212> PRT
<213> 人工
<220>
<223> CNP37 MMP ELP1-120 融合 PE09326
<400> 129
Gln Glu His Pro Asn Ala Arg Lys Tyr Lys Gly Ala Asn Lys Lys Gly
1 5 10 15
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser Met
20 25 30
Ser Gly Leu Gly Cys Pro Leu Gly Leu Trp Ala Gly Val Pro Gly Val
35 40 45
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
50 55 60
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
65 70 75 80
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
85 90 95
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
100 105 110
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
115 120 125
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
130 135 140
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
145 150 155 160
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
165 170 175
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
180 185 190
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
195 200 205
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
210 215 220
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
225 230 235 240
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
245 250 255
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
260 265 270
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
275 280 285
Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
290 295 300
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val
305 310 315 320
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
325 330 335
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly
340 345 350
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
355 360 365
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
370 375 380
Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
385 390 395 400
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
405 410 415
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
420 425 430
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val
435 440 445
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
450 455 460
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
465 470 475 480
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
485 490 495
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
500 505 510
Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
515 520 525
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly
530 535 540
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
545 550 555 560
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
565 570 575
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
580 585 590
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
595 600 605
Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
610 615 620
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
625 630 635 640
Pro Gly Gly Gly Val Pro Gly Trp Pro
645
<210> 130
<211> 1947
<212> DNA
<213> 人工
<220>
<223> CNP37 MMP ELP1-120 融合 PE09326
<400> 130
caggaacatc cgaacgcgcg taaatataaa ggtgcgaaca aaaaaggcct gagcaaaggc 60
tgctttggcc tgaaactgga tcgcattggc agcatgagcg gcctgggctg cccgctgggc 120
ctgtgggcgg gtgtaccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 180
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 240
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 300
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 360
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 420
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 480
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 540
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 600
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 660
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 720
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 780
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 840
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 900
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 960
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1020
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 1080
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 1140
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 1200
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 1260
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1320
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 1380
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 1440
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 1500
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 1560
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1620
ccgggtggcg gtgtgccggg cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg 1680
ccgggcgcag gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta 1740
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg cgtgggtgtt 1800
ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag gtgttcctgg tgtaggtgtg 1860
ccgggtgttg gtgtgccggg tgttggtgta ccaggtggcg gtgttccggg tgcaggcgtt 1920
ccgggtggcg gtgtgccggg ctggccg 1947
<210> 131
<211> 787
<212> PRT
<213> 人工
<220>
<223> ELP1-120 FGF21 融合 PE9183
<400> 131
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
1 5 10 15
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
35 40 45
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
85 90 95
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
115 120 125
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
130 135 140
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
165 170 175
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
180 185 190
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
225 230 235 240
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
260 265 270
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
305 310 315 320
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
355 360 365
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
405 410 415
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
435 440 445
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
485 490 495
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
530 535 540
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
580 585 590
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Gly Pro His Pro
595 600 605
Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln
610 615 620
Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu
625 630 635 640
Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu
645 650 655
Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu
660 665 670
Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu
675 680 685
Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu
690 695 700
Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu
705 710 715 720
Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro
725 730 735
Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro
740 745 750
Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser
755 760 765
Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser
770 775 780
Tyr Ala Ser
785
<210> 132
<211> 2361
<212> DNA
<213> 人工
<220>
<223> ELP1-120 FGF21 融合 PE9183
<400> 132
atggtaccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 60
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 120
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 180
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 240
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 300
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 360
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 420
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 480
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 540
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 600
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 660
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 720
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 780
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 840
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 900
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 960
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1020
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1080
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1140
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1200
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1260
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1320
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1380
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1440
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1500
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1560
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1620
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1680
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1740
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1800
ggtgtgccgg gcgggccgca cccgatcccg gacagctctc cgctgctgca gtttggcggt 1860
caggtacgtc agcgttacct gtatactgac gacgcccagc agaccgaagc tcacctggag 1920
atccgcgaag acggtaccgt aggcggtgct gcagatcaat ctcctgaatc tctgctgcag 1980
ctgaaggcac tgaaaccggg cgttatccaa atcctgggtg ttaaaacttc tcgtttcctg 2040
tgccagcgcc cggatggtgc actgtacggt tctctgcatt tcgacccgga ggcctgctct 2100
ttccgtgaac tgctgctgga agatggttac aatgtatacc aatctgaggc acacggtctg 2160
ccgctgcacc tgcctggcaa caaatctccg catcgtgacc cggccccgcg cggtccagcc 2220
cgctttctgc cgctgccggg tctgccgccg gctccaccag aaccgcctgg tatcctggcg 2280
cctcagccac ctgatgttgg ctcctccgac ccgctgtcta tggtcggtcc gagccaaggc 2340
cgttccccaa gctacgccag t 2361
<210> 133
<211> 817
<212> PRT
<213> 人工
<220>
<223> GLP1 ELP1-120 FGF21 双重融合 PE9193
<400> 133
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Val
20 25 30
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
35 40 45
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
65 70 75 80
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
85 90 95
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
100 105 110
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
115 120 125
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
130 135 140
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
145 150 155 160
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
165 170 175
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
180 185 190
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
210 215 220
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val
225 230 235 240
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val
260 265 270
Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
290 295 300
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly
305 310 315 320
Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
325 330 335
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
340 345 350
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
355 360 365
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly
370 375 380
Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
385 390 395 400
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
405 410 415
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
420 425 430
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
435 440 445
Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
450 455 460
Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly
465 470 475 480
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
485 490 495
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
500 505 510
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
515 520 525
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
530 535 540
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
565 570 575
Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
580 585 590
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro
595 600 605
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
610 615 620
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Gly Pro His Pro Ile Pro
625 630 635 640
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
645 650 655
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
660 665 670
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
675 680 685
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
690 695 700
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
705 710 715 720
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
725 730 735
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
740 745 750
His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
755 760 765
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu
770 775 780
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
785 790 795 800
Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
805 810 815
Ser
<210> 134
<211> 2451
<212> DNA
<213> 人工
<220>
<223> GLP1 ELP1-120 FGF21 双重融合 PE9193
<400> 134
catggcgaag gtacctttac aagcgatgtt agttcatatc tggagggcca ggcggcaaag 60
gaatttattg cgtggctggt gaaaggccgc ggcgtgccgg gcgtgggtgt tccgggcgtg 120
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 180
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 240
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 300
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 360
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 420
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 480
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 540
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 600
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 660
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 720
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 780
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 840
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 900
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 960
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1020
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1080
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1140
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1200
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1260
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1320
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1380
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1440
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1500
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1560
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgtgggtgt tccgggcgtg 1620
ggtgttccgg gtggcggtgt gccgggcgca ggtgttcctg gtgtaggtgt gccgggtgtt 1680
ggtgtgccgg gtgttggtgt accaggtggc ggtgttccgg gtgcaggcgt tccgggtggc 1740
ggtgtgccgg gcgtgggtgt tccgggcgtg ggtgttccgg gtggcggtgt gccgggcgca 1800
ggtgttcctg gtgtaggtgt gccgggtgtt ggtgtgccgg gtgttggtgt accaggtggc 1860
ggtgttccgg gtgcaggcgt tccgggtggc ggtgtgccgg gcgggccgca cccgatcccg 1920
gacagctctc cgctgctgca gtttggcggt caggtacgtc agcgttacct gtatactgac 1980
gacgcccagc agaccgaagc tcacctggag atccgcgaag acggtaccgt aggcggtgct 2040
gcagatcaat ctcctgaatc tctgctgcag ctgaaggcac tgaaaccggg cgttatccaa 2100
atcctgggtg ttaaaacttc tcgtttcctg tgccagcgcc cggatggtgc actgtacggt 2160
tctctgcatt tcgacccgga ggcctgctct ttccgtgaac tgctgctgga agatggttac 2220
aatgtatacc aatctgaggc acacggtctg ccgctgcacc tgcctggcaa caaatctccg 2280
catcgtgacc cggccccgcg cggtccagcc cgctttctgc cgctgccggg tctgccgccg 2340
gctccaccag aaccgcctgg tatcctggcg cctcagccac ctgatgttgg ctcctccgac 2400
ccgctgtcta tggtcggtcc gagccaaggc cgttccccaa gctacgccag t 2451
Claims (141)
1.持续释放药物制剂,其包含:
用于全身给药的治疗剂,该治疗剂包含蛋白活性剂和至少60个选自SEQ ID NO:1-13中任一个的弹性蛋白样肽(ELP)结构单元,
其中所述蛋白活性剂选自爱帕琳肽、精氨酸酶、C-型利钠肽(CNP)、胰高血糖素样肽(GLP)-1受体拮抗剂、胰高血糖素样肽(GLP)-2受体激动剂、铁调素、胰岛素样生长因子-1(IGF-1)、尿扩张素、胸腺素β4、TNF-相关的凋亡-诱导配体(TRAIL)、FGF21、或它们的片段或衍生物。
2.权利要求1的药物制剂,其中所述制剂在施用后提供从注射位点的缓慢吸收。
3.权利要求2的药物制剂,其中相比于在不存在形成可逆基质的氨基酸序列的情况下活性剂的PK曲线,所述制剂在施用后提供平的PK曲线。
4.权利要求3的药物制剂,其中所述PK曲线具有低峰谷比(Cmax比Cmin)和延迟的或较晚的Tmax。
5.权利要求1至4任一项的药物制剂,其中在体温形成的可逆基质随着蛋白质浓度降低而逆转。
6.权利要求1的药物制剂,其中所述ELP包含SEQ ID NO:3,其中X选自Val、Gly和Ala。
7.权利要求6的药物制剂,其中各个X选自V、G和A,且其中V:G:A的比例选自
a)5:3:2;
b)7:2:0;
c)7:0:2;
d)6:0:3;
e)5:2:2;和
f)10:0:0。
8.权利要求1的药物制剂,其中所述ELP包含SEQ ID NO:13,其中X选自Val、Gly和Ala。
9.权利要求8的药物制剂,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:0:4。
10.权利要求6的药物制剂,其中所述ELP包含40至180个VPGXG(SEQ ID NO:3)重复单元,其中各个X选自V、G和A,且其中V:G:A的比例选自:
a)5:3:2;
b)7:2:0;
c)7:0:2;
d)6:0:3;和
e)5:2:2。
11.权利要求10的药物制剂,其中X选自Val、Gly和Ala,其比例为约6:0:3。
12.权利要求8的药物制剂,其中所述ELP包含40至180个XPGVG(SEQ ID NO:13)重复单元,其中各个X选自V、G和A,且其中V:G:A的比例可为约5:0:4。
13.权利要求1至12任一项的药物制剂,其中所述受试者为人。
14.权利要求1至12任一项的药物制剂,其中所述受试者为非人哺乳动物。
15.权利要求1的药物制剂,其中所述治疗剂为蛋白活性剂和ELP的重组融合蛋白。
16.权利要求1的药物制剂,其中所述蛋白活性剂具有的循环半衰期的范围为约30秒至约10小时,或约30秒至约1小时。
17.权利要求16的药物制剂,其中所述制剂为包含以下至少两种的共配制剂:爱帕琳肽、精氨酸酶、CNP、GLP-1受体拮抗剂、GLP-2受体激动剂、铁调素、IGF-1、尿扩张素、胸腺素β4、和TRAIL、FGF21,或它们的片段或衍生物。
18.权利要求1至14和16至17任一项的药物制剂,其中所述治疗剂为蛋白活性剂和ELP的化学缀合物。
19.权利要求1至18任一项的药物制剂,其中所述治疗剂存在量的范围为约0.5mg/mL至约200mg/mL。
20.权利要求19的药物制剂,其中所述治疗剂存在量的范围为约30mg/mL至约150mg/mL。
21.权利要求20的药物制剂,其中所述治疗剂存在量的范围为约50mg/mL至约125mg/mL,或约75mg/mL至约110mg/mL。
22.权利要求21的药物制剂,其中所述治疗剂存在的量为约100mg/mL。
23.权利要求1至22任一项所述的药物组合物,其中所述治疗剂在储存条件不形成相转变的基质。
24.权利要求23所述的药物组合物,其中所述储存条件为低于约40℃、或低于约37℃、低于约30℃、低于约27℃、低于约25℃、低于约0℃、低于约-15℃、或低于约-60℃。
25.权利要求24的药物制剂,其中所述制剂在储存条件下稳定超过1个月。
26.权利要求25的药物制剂,其中所述制剂在选自以下的温度下稳定超过约1个月:
a.约25℃;
b.约2℃;
c.约8℃;
d.约-15℃;和
e.约-80℃。
27.权利要求1-26任一项的药物制剂,其中所述制剂包含氯化钙、氯化镁、氯化钾、磷酸二氢钾、氯化钠、聚山梨酯20、聚山梨酯80、磷酸钠、磷酸二氢钠、组氨酸和磷酸氢二钠中的两种或更多种。
28.权利要求27的药物制剂,其中所述制剂包含磷酸钠、氯化钠和聚山梨酯20。
29.权利要求27的药物制剂,其中所述制剂包含氯化钠和组氨酸。
30.权利要求28的药物制剂,其中所述制剂包含10mM磷酸钠、110mM氯化钠和0.1%聚山梨酯20。
31.权利要求1至30任一项的药物制剂,其中所述制剂包装成预先设定剂量的笔或注射器的形式,用于约每周一次、约每周两次、或每个月1至8次给药。
32.持续释放的药物制剂,其包含:
治疗剂,该治疗剂包含蛋白活性剂和ELP氨基酸序列,所述ELP氨基酸序列包含60至180个VPGXG(SEQ ID NO:3)或XPGVG(SEQ ID NO:13)重复单元,其中各个X选自V、G和A,且其中所述ELP具有的转变温度为26℃至37℃,
其中所述蛋白活性剂为爱帕琳肽、精氨酸酶、C-型利钠肽(CNP)、胰高血糖素样肽(GLP)-1受体拮抗剂、胰高血糖素样肽(GLP)-2受体激动剂、铁调素、胰岛素样生长因子-1(IGF-1)、尿扩张素、胸腺素β4、TNF-相关的凋亡-诱导配体(TRAIL)、FGF21、或它们的片段或衍生物。
33.权利要求32的药物制剂,其中所述制剂在施用后提供从注射位点的缓慢吸收。
34.权利要求33的药物制剂,其中相比于不存在所述氨基酸序列的情况下活性剂的PK曲线,所述制剂在施用后提供平的PK曲线。
35.权利要求33的药物制剂,其中所述PK曲线具有低峰谷比(Cmax比Cmin)和延迟的或较晚的Tmax。
36.权利要求32至35任一项的药物制剂,其中在体温形成的可逆基质随着蛋白质浓度降低而逆转。
37.权利要求32至36任一项的药物制剂,其中V、G和A为选自以下的比例:
a)5:3:2;
b)7:2:0;
c)7:0:2;
d)6:0:3;
e)5:2:2;和
f)5:0:4。
38.权利要求32的药物制剂,其中所述ELP包括包含至少60个VPGXG(SEQ ID NO:3)重复单元的ELP单元,其中各个X为V。
39.权利要求32的药物制剂,其中所述治疗剂为蛋白活性剂和所述氨基酸序列的重组融合蛋白。
40.权利要求32的药物制剂,其中所述蛋白活性剂具有的循环半衰期的范围为约30秒至约10小时,或约30秒至约1小时。
41.权利要求32的药物制剂,其中所述蛋白活性剂选自爱帕琳肽、精氨酸酶、CNP、GLP-1受体拮抗剂、GLP-2受体激动剂、铁调素、IGF-1、尿扩张素、胸腺素β4、TRAIL、FGF21、或它们的片段或衍生物。
42.权利要求32的药物制剂,其中所述制剂为包含以下至少两种的共配制剂:爱帕琳肽、精氨酸酶、CNP、GLP-1受体拮抗剂、GLP-2受体激动剂、铁调素、IGF-1、尿扩张素、胸腺素β4、TRAIL、FGF21、或它们的片段或衍生物。
43.权利要求32至38和40至42任一项的药物制剂,其中所述治疗剂为所述蛋白活性剂和所述ELP氨基酸序列的化学缀合物。
44.权利要求32至43任一项的药物制剂,其中所述治疗剂存在量的范围为约0.5mg/mL至约200mg/mL。
45.权利要求44的药物制剂,其中所述治疗剂存在量的范围为约30mg/mL至约150mg/mL。
46.权利要求45的药物制剂,其中所述治疗剂存在量的范围为约50mg/mL至约125mg/mL,或范围为约75mg/mL至约110mg/mL。
47.权利要求46的药物制剂,其中所述治疗剂存在量的范围为约100mg/mL。
48.权利要求32至47任一项所述的药物组合物,其中所述治疗剂在储存条件下不形成基质。
49.权利要求48所述的药物组合物,其中所述储存条件为低于约40℃、或低于约37℃、或低于约30℃、低于约27℃、或低于约25℃、低于约0℃、低于约-15℃、或低于约-60℃。
50.权利要求32至49任一项所述的药物制剂,其中所述制剂包含氯化钙、氯化镁、氯化钾、磷酸二氢钾、氯化钠、氯化钠、聚山梨酯20、聚山梨酯80、磷酸钠、磷酸二氢钠、组氨酸和磷酸氢二钠中的两种或更多种。
51.权利要求50的药物制剂,其中所述制剂包含磷酸钠、氯化钠和聚山梨酯20。
52.权利要求50的药物制剂,其中所述制剂包含氯化钠和组氨酸。
53.权利要求51的药物制剂,其中所述制剂包含10mM磷酸钠、110mM氯化钠和0.1%聚山梨酯20。
54.权利要求32至53任一项的药物制剂,其中所述制剂包装成预先设定剂量的笔或注射器的形式,用于每周一次、每周两次、或每个月1至8次给药。
55.递送治疗剂的持续释放方案的方法,包括向需要的受试者给药权利要求1至54任一项的制剂。
56.权利要求55所述的方法,其中所述治疗剂每个月给药约1至约8次。
57.权利要求55至56任一项所述的方法,其中所述制剂约每周给药。
58.权利要求55至57任一项所述的方法,其中所述制剂皮下或肌内给药。
59.权利要求55至58任一项所述的方法,其中所述给药位点不是病理位点。
60.权利要求1的药物制剂,其中所述蛋白活性剂为人爱帕琳肽且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
61.权利要求60的药物制剂,其中所述ELP融合至人爱帕琳肽的C端。
62.权利要求60的药物制剂,其中所述ELP融合至人爱帕琳肽的N端。
63.权利要求60的药物制剂,其中所述人爱帕琳肽为SEQ ID NO:39。
64.权利要求60的药物制剂,其中所述人爱帕琳肽为SEQ ID NO:41。
65.权利要求60的药物制剂,其中所述人爱帕琳肽为SEQ ID NO:42。
66.权利要求60的药物制剂,其中所述人爱帕琳肽为SEQ ID NO:43。
67.权利要求60的药物制剂,其中所述人爱帕琳肽为SEQ ID NO:44。
68.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:40。
69.权利要求1的药物制剂,其中所述蛋白活性剂为人精氨酸酶且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
70.权利要求69的药物制剂,其中所述ELP融合至人精氨酸酶的C端。
71.权利要求69的药物制剂,其中所述ELP融合至人精氨酸酶的N端。
72.权利要求69的药物制剂,其中所述人精氨酸酶为SEQ ID NO:45。
73.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:46。
74.权利要求1的药物制剂,其中所述蛋白活性剂为人CNP且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
75.权利要求74的药物制剂,其中所述ELP融合至人CNP的C端。
76.权利要求74的药物制剂,其中所述ELP融合至人CNP的N端。
77.权利要求74的药物制剂,其中所述人CNP为SEQ ID NO:47。
78.权利要求74的药物制剂,其中所述人CNP为SEQ ID NO:49。
79.权利要求74的药物制剂,其中所述人CNP为SEQ ID NO:51。
80.权利要求74的药物制剂,其中所述人CNP为SEQ ID NO:52。
81.权利要求74-80任一项的药物制剂,其中所述CNP和ELP通过包含蛋白酶切割位点的接头分开。
82.权利要求81的药物制剂,其中在所述蛋白酶切割位点的切割使得能够体内释放CNP。
83.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:48。
84.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:83。
85.权利要求1的药物制剂,其中所述蛋白活性剂为人GLP-1受体拮抗剂且所述ELP为SEQ ID NO:14。
86.权利要求85的药物制剂,其中所述ELP融合至人GLP-1受体拮抗剂的C端。
87.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:54。
88.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:64。
89.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:65。
90.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:27。
91.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:28。
92.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:60。
93.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:61。
94.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:62。
95.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:63。
96.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:66。
97.权利要求85的药物制剂,其中所述人GLP-1受体拮抗剂为SEQ ID NO:67。
98.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:57。
99.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:58。
100.权利要求1至30任一项的药物制剂,其中所述治疗剂为SEQ ID NO:59。
101.权利要求1的药物制剂,其中所述蛋白活性剂为人GLP-2受体激动剂且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
102.权利要求101的药物制剂,其中所述ELP融合至人GLP-2受体激动剂的C端。
103.权利要求101的药物制剂,其中所述ELP融合至人GLP-2受体激动剂的N端。
104.权利要求101的药物制剂,其中所述人GLP-2受体激动剂为SEQ ID NO:68。
105.权利要求101的药物制剂,其中所述人GLP-2受体激动剂为SEQ ID NO:70。
106.权利要求101的药物制剂,其中所述人GLP-2受体激动剂为SEQ ID NO:74,其中X为A、G、L、I或V。
107.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:69。
108.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:71。
109.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:73。
110.权利要求1的药物制剂,其中所述蛋白活性剂为人铁调素且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
111.权利要求110的药物制剂,其中所述ELP融合至人铁调素的C端。
112.权利要求110的药物制剂,其中所述ELP融合至人铁调素的N端。
113.权利要求110的药物制剂,其中所述人铁调素为SEQ ID NO:75。
114.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:76。
115.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:77。
116.权利要求1的药物制剂,其中所述蛋白活性剂为IGF-1且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
117.权利要求1的药物制剂,其中所述蛋白活性剂为人IGF-1且所述ELP包含至少60XPGVG(SEQ ID NO:13)重复单元。
118.权利要求116或权利要求117的药物制剂,其中所述ELP融合至人IGF-1的C端。
119.权利要求116或权利要求117的药物制剂,其中所述ELP融合至人IGF-1的N端。
120.权利要求116或权利要求117的药物制剂,其中所述人IGF-1为SEQ ID NO:78。
121.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:79。
122.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:80。
123.权利要求1的药物制剂,其中所述蛋白活性剂为人尿扩张素且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
124.权利要求124的药物制剂,其中所述ELP融合至人尿扩张素的C端。
125.权利要求124的药物制剂,其中所述ELP融合至人尿扩张素的N端。
126.权利要求124的药物制剂,其中所述人尿扩张素为SEQ ID NO:84。
127.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:85。
128.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:86。
129.权利要求1的药物制剂,其中所述蛋白活性剂为人胸腺素β4且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
130.权利要求129的药物制剂,其中所述ELP融合至人胸腺素β4的C端。
131.权利要求129的药物制剂,其中所述ELP融合至人胸腺素β4的N端。
132.权利要求129的药物制剂,其中所述人胸腺素β4为SEQ ID NO:89。
133.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:90。
134.权利要求1的药物制剂,其中所述蛋白活性剂为人TRAIL且所述ELP包含至少60个VPGXG(SEQ ID NO:3)重复单元。
135.权利要求134的药物制剂,其中所述ELP融合至人TRAIL的C端。
136.权利要求134的药物制剂,其中所述ELP融合至人TRAIL的N端。
137.权利要求134的药物制剂,其中所述人TRAIL为SEQ ID NO:89。
138.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:92。
139.权利要求1的药物制剂,其中所述治疗剂为SEQ ID NO:98。
140.一种治疗性蛋白,其包含:
蛋白活性剂和至少60个选自SEQ ID NO:1-13任一个的弹性蛋白样肽(ELP)结构单元,
其中所述蛋白活性剂选自爱帕琳肽、精氨酸酶、C-型利钠肽(CNP)、胰高血糖素样肽(GLP)-1受体拮抗剂、胰高血糖素样肽(GLP)-2受体激动剂、铁调素、胰岛素样生长因子-1(IGF-1)、尿扩张素、胸腺素β4、TNF-相关的凋亡-诱导配体(TRAIL)、FGF21、或它们的片段或衍生物。
141.一种治疗性蛋白,其包含:
治疗剂,该治疗剂包含蛋白活性剂和ELP氨基酸序列,所述ELP氨基酸序列包含60至180个VPGXG(SEQ ID NO:3)或XPGVG(SEQ ID NO:13)重复单元,其中各个X选自V、G和A,且其中所述ELP具有的转变温度为26℃至37℃,
其中所述蛋白活性剂为爱帕琳肽、精氨酸酶、C-型利钠肽(CNP)、胰高血糖素样肽(GLP)-1受体拮抗剂、胰高血糖素样肽(GLP)-2受体激动剂、铁调素、胰岛素样生长因子-1(IGF-1)、尿扩张素、胸腺素β4、TNF-相关的凋亡-诱导配体(TRAIL)、FGF21、或它们的片段或衍生物。
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CA3021644A1 (en) | 2017-11-09 |
MX2018013546A (es) | 2019-04-22 |
WO2017192449A1 (en) | 2017-11-09 |
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