CN108359005A - 非洲爪蟾glp-1类似物及其用途 - Google Patents
非洲爪蟾glp-1类似物及其用途 Download PDFInfo
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Abstract
本发明涉及一种非洲爪蟾GLP‑1类似物及其合成方法和应用。通过对非洲爪蟾GLP‑1的侧链和及C末端进行结构修饰，得到具有更高降糖活性和更长药理作用时间的非洲爪蟾GLP‑1类似物。本发明的非洲爪蟾GLP‑1类似物的生物活性显著提高，具有很强的长效降糖和减肥作用。
Description
技术领域
本发明涉及一种非洲爪蟾胰高血糖素样肽-1类似物及其应用
背景技术
糖尿病(Diabetes mellitus，DM)是一组由遗传和环境等多种病因引起以慢性高血糖为特征的代谢性疾病群。由于胰岛素分泌相对或绝对不足；或胰岛素作用缺陷引起糖、蛋白质、脂肪、水和电解质等一系列代谢紊乱。持续高血糖是基本特征。久病可引起多系统损害，导致眼、肾、神经、及心脑血管、下肢等器官的慢性并发症。2016年3月6日，世界卫生组织首次发布全球糖尿病报告，显示全球糖尿病成年人患者近40年内增加了3倍，其中多数生活在发展中国家。报告显示，中国成年人患糖尿病率接近10％。糖尿病分1型糖尿和2型糖尿病和妊娠期糖尿病和其他特殊类型糖尿病。研究发现2型糖尿病患者占90％以上。目前糖尿病的治疗方法主要包括口服降糖药物和胰岛素治疗，但这些方法在长期的治疗中会产生毒副作用。
胰高血糖素样肽-1(Glucagon-Like Peptide-1，GLP-1)具有保护β细胞的作用，GLP-1可作用于胰岛β细胞，促进胰岛素基因的转录、胰岛素的合成和分泌，并可刺激胰岛β细胞的增殖和分化，抑制胰岛β细胞凋亡，增加胰岛β细胞数量。此外，GLP-1还可作用于胰岛α细胞，强烈地抑制胰高血糖素的释放，并作用于胰岛δ细胞，促进生长抑素的分泌，生长抑素又可作为旁分泌激素参与抑制胰高血糖素的分泌。研究证明，GLP-1可通过多种机制明显地改善2型糖尿病动物模型或患者的血糖情况，其中促进胰岛β细胞的再生和修复，增加胰岛β细胞数量的作用尤为显著，这为2型糖尿病的治疗提供了一个非常好的前景。然而天然GLP-1存在局限性，即它的半衰期特别短，分泌2～3分钟后就会被二肽基肽酶 (DPP-IV)降解，即使外源性给予GLP-1，也同样很快会被DPP-IV降解。另外，内源性GLP-1还会被肾脏快速滤过代谢，其体内半衰期仅为2-3min。因此，需要我们寻找和GLP-1具有相似的生物活性，但能在体内长效作用的新型GLP-1 受体激动剂。
非洲爪蟾GLP-1(XenGLP-1)的降糖活性优于天然GLP-1，另外其特殊的氨基酸序列使其具有更好的体内稳定性，是一个优良的先导多肽。天然产物中的脂肪酸类化合物有比较强的血清蛋白结合率，血清白蛋白结合以后的药物与游离药物在体内产生平衡，缓慢释放实现长效化。同时血清白蛋白结合药物不易被肾小球滤过，可以避免肾脏的滤过代谢。所以，我们设计了以长链脂肪酸为母核的脂肪酸类化合物，通过谷氨酸(γ-Glu)或短链聚乙二醇-谷氨酸(PEG-γ-Glu)与 XenGLP-1肽链相连接。
发明内容
本发明涉及一类非洲爪蟾胰高血糖素样肽-1(XenGLP-1)类似物，其结构具有以下形式：
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala -Xaa2-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Xaa3-Gly-Xaa4-Xaa5(SEQ.ID NO:1)
其中：
Xaa1:Ala，Gly或Aib；
Xaa2:Lys(fatty acid analog)或Lys；
Xaa3:Lys(fatty acid analog)或Lys；
Xaa4:Lys(fatty acid analog)或Lys；
Xaa5:Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2， Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH， Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser
-Lys-Lys-Lys-Lys-Lys-Lys-OH，-OH或-NH2；
前提是所述序列不是
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu
-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-NH2,
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-
Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-I le-Lys-Gly-Lys-OH，
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala -Lys
-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2，His-Xaa1
-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu- Phe-Ile-Glu-
Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH， His-Xaa1-Glu-Gly-Thr-Tyr-
Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-L eu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2或His-Xaa1-Glu-Gly-Thr-
Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-T rp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys- OH；
以及该类似物所成的可药用的盐、溶剂化物、螯合物或非共价复合物，基于该类似物基础上的药物前体，或上述形式类似物的任意混合物。
其中Lys(fatty acid analog)选自
这里：n选自12～20。
其中最优选的Lys(fatty acid analog)结构为
优选的XenGLP-1类似物的氨基酸序列如SEQ.ID NO:2-31所示。
本发明还提供了一种药物组合物，包括治疗有效量的至少一种上述 XenGLP-1类似物或其药学上可接受的盐、溶剂化物、螯合物或非共价复合物，基于该类似物基础上的药物前体，或上述形式类似物的任意混合物，和一种或者多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步提供了上述XenGLP-1类似物或其药学上可接受的盐或药物组合物在药物中的应用。
本发明涉及的XenGLP-1类似物，以liraglutide及semaglutide为对照，在体外实验中利用高度表达GLP-1受体的HEK293细胞模型，评价其体外受体激动活性。并利用人血浆温敷，评价其体外稳定性。在体内实验中，以糖尿病小鼠及肥胖小鼠为实验模型，鉴定其长效降血糖及减肥效果。体外和体内实验结果表明，本发明提供的XenGLP-1类似物具有极高的体外稳定性，并在降血糖作用时间及减肥效果方面，显著的优于liraglutide及semaglutide。
本发明的优点在于：
本发明所涉及的非洲爪蟾GLP-1(XenGLP-1)类似物，由于其特殊的氨基酸序列，其体内稳定性显著的优于天然GLP-1，进一步利用脂肪酸修饰所得到的 XenGLP-1类似物，其体内降糖作用时间和减肥作用显著优于以GLP-1肽链为主体的liraglutide及semaglutide，可以广泛的应用于糖尿病及肥胖的治疗。
附图说明
上文对本发明做了一般性描述，下面附图用于说明本发明的具体实施方案。其中：
图1显示的是XenGLP-1类似物体外血浆稳定性实验的降解图；
图2显示的是XenGLP-1类似物长效降糖实验的血糖-时间曲线图；
图3显示的是XenGLP-1类似物降低体重实验的体重变化曲线图。
具体实施方式
在本说明书全文中采用以下缩写：
DMF：二甲基甲酰胺；DCM：二氯甲烷；Fmoc：N-9-芴甲氧羰基；DIC： N,N’-二异丙基碳二亚胺；HOBT：1-羟基-苯并三氮唑；TFA：三氟乙酸；EDT：二巯基乙烷；HPLC：高效液相色谱；ESI-MS：电喷雾质谱；LC-MS：液质联用质谱；Gly：甘氨酸；Ser：丝氨酸；Ala：丙氨酸；Thr：苏氨酸；Val：缬氨酸； Ile：异亮氨酸；Leu：亮氨酸；Tyr：酪氨酸；Phe：苯丙氨酸；His：组氨酸；Pro：脯氨酸；Asp：天门冬氨酸；Met：蛋氨酸；Glu：谷氨酸；Trp：色氨酸；Lys：赖氨酸；Arg：精氨酸；Asn：天冬酰胺；Gln：谷氨酰胺；Cys：半胱氨酸。
本发明是通过下列实施例来进行说明的，但这些实施例不做任何限制本发明的解释。
实施实例1
(1)树脂的溶胀
称取担载量为0.382mmol/g的Rink Amide MBHA树脂0.262g(0.1mmol)，放入25mL的反应器中，用7mL的DCM和甲醇交替清洗树脂1次，7mL的 DCM清洗树脂2次，然后用7mL的DCM溶胀树脂1h，最后用7mL DMF清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入多肽合成仪，加入7mL 20％哌啶/DMF室温反应5min，滤去脱保护溶液，7mL DMF清洗树脂一次，再加入7mL 20％哌啶/DMF脱保护清洗树脂15min，最后7mL DMF清洗树脂4次，每次1.5min，得到脱除Fmoc 保护基的Rink树脂。
(3)Fmoc-Lys-Rink amide-MBHA Resin的合成
称Fmoc-Lys(Boc)-OH(0.4mmol)，用3mL 10％DMF/DMSO溶解，加入2 ml DIC/HOBt(0.4mmol/0.44mmol)，搅拌30min后，将活化好的氨基酸加入反应器中，室温震荡反应2h，滤去反应液后用7mL DMF清洗树脂4次。
(5)肽链的延长
按照肽链的序列，重复上述脱保护和耦合的步骤依次连接上相应的氨基酸，直至肽链合成完毕。其中脂肪酸化位点的Lys使用具有特殊侧链保护基的 Fmoc-Lys(Dde)-OH，N末端的His使用的是Boc-His(Boc)-OH。
(6)Lys定点脂肪酸化修饰
肽链合成完毕后，加入7mL 2％水合肼/DMF选择性脱除脂肪酸化位点Lys 的Dde保护基，Dde保护基脱除后加入0.4mmol的Fmoc-Glu-OtBu，0.4mmol的 DIC及0.44mmol的HOBt，震荡反应2h。然后使用相同方法脱除Fmoc后，加入0.4mmol的棕榈酸小分子，0.4mmol的DIC及0.44mmol的HOBt缩合反应 2h，滤去反应液后用7mL DMF清洗树脂4次。
(7)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中，使用切割剂Reagent R(TFA/ 苯甲硫醚/苯酚/EDT，90:5:3:2，V/V)5mL切割树脂，在油浴中恒温30℃反应2 h，切割液倾入40ml冰乙醚，冷冻离心后粗品用15ml冰乙醚洗涤3次，最后用氮气吹干，得到粗肽。
(8)多肽的纯化
将目标多肽粗品溶于水中，浓度为10mg/mL，用0.25μm微孔滤膜过滤后进岛津制备型反相HPLC系统纯化。色谱条件为C18反相制备柱(250mm×20 mm，12μm)；流动相A：0.1％TFA/水(V/V)，流动相B：乙醇(V/V)；流速为15mL/min；检测波长为214nm。采用线性梯度(55％B～90％B/30min)洗脱，收集目标峰冻干得纯品。理论相对分子质量为3838.3。ESI-MSm/z:calu [M+3H]3+1290.4,[M+4H]4+968.1；found[M+3H]3+1290.2,[M+4H]4+968.0。
实施例2～19
根据实施例1所述的方法，根据相应的序列和侧链合成得到实施例2～30的非洲爪蟾胰高血糖素样肽-1(XenGLP-1)类似物，通过ESI-MS确证各自的分子量。
实施例2
理论相对分子质量为3838.3。ESI-MS m/z:calu[M+3H]3+1290.4,[M+4H]4+968.1；found[M+3H]3+1290.6,[M+4H]4+968.5。
实施例3
理论相对分子质量为3838.3。ESI-MS m/z:calu[M+3H]3+1290.4,[M+4H]4+968.1；found[M+3H]3+1290.4,[M+4H]4+968.3。
实施例4
理论相对分子质量为3896.4。ESI-MS m/z:calu[M+3H]3+1299.8,[M+4H]4+975.1；found[M+3H]3+1300.2,[M+4H]4+975.6。
实施例5
理论相对分子质量为3896.4。ESI-MS m/z:calu[M+3H]3+1299.8,[M+4H]4+975.1；found[M+3H]3+1300.0,[M+4H]4+975.3。
实施例6
理论相对分子质量为3896.4。ESI-MS m/z:calu[M+3H]3+1299.8,[M+4H]4+975.1；found[M+3H]3+1299.9,[M+4H]4+975.1。
实施例7
理论相对分子质量为4646.2。ESI-MS m/z:calu[M+4H]4+1162.6,[M+5H]5+930.2；found[M+4H]4+1162.9,[M+5H]5+930.4。
实施例8
理论相对分子质量为4646.2。ESI-MS m/z:calu[M+4H]4+1162.6,[M+5H]5+930.2；found[M+4H]4+1162.5,[M+5H]5+930.2。
实施例9
理论相对分子质量为4646.2。ESI-MS m/z:calu[M+4H]4+1162.6,[M+5H]5+930.2；found[M+4H]4+1162.7,[M+5H]5+930.7。
实施例10
理论相对分子质量为4674.2。ESI-MS m/z:calu[M+4H]4+1169.6,[M+5H]5+935.8；found[M+4H]4+1169.9,[M+5H]5+936.1。
实施例11
理论相对分子质量为4674.2。ESI-MS m/z:calu[M+4H]4+1169.6,[M+5H]5+935.8；found[M+4H]4+1170.2,[M+5H]5+936.3。
实施例12
理论相对分子质量为4674.2。ESI-MS m/z:calu[M+4H]4+1169.6,[M+5H]5+935.8；found[M+4H]4+1169.4,[M+5H]5+935.7。
实施例13
理论相对分子质量为5318.1。ESI-MS m/z:calu[M+4H]4+1330.5[M+5H]5+1064.6；found[M+4H]4+1330.9,[M+5H]5+1064.8。
实施例14
理论相对分子质量为5318.1。ESI-MS m/z:calu[M+4H]4+1330.5[M+5H]5+1064.6；found[M+4H]4+1330.5,[M+5H]5+1064.7。
实施例15
理论相对分子质量为5318.1。ESI-MS m/z:calu[M+4H]4+1330.5[M+5H]5+1064.6；found[M+4H]4+1330.7,[M+5H]5+1064.6。
实施例16
理论相对分子质量为5346.2。ESI-MS m/z:calu[M+4H]4+1337.6,[M+5H]5+1070.2；found[M+4H]4+1337.9,[M+5H]5+1070.5。
实施例17
理论相对分子质量为5346.2。ESI-MS m/z:calu[M+4H]4+1337.6,[M+5H]5+1070.2；found[M+4H]4+1337.5,[M+5H]5+1070.3。
实施例18
理论相对分子质量为5346.2。ESI-MS m/z:calu[M+4H]4+1337.6,[M+5H]5+1070.2；found[M+4H]4+1337.5,[M+5H]5+1070.3。
实施例19
理论相对分子质量为4158.6。ESI-MS m/z:calu[M+4H]4+1040.6,[M+5H]5+832.7；found[M+4H]4+1040.9,[M+5H]5+832.8。
实施例20
理论相对分子质量为4158.6。ESI-MS m/z:calu[M+4H]4+1040.6,[M+5H]5+832.7；found[M+4H]4+1040.7,[M+5H]5+832.9。
实施例21
理论相对分子质量为4936.5。ESI-MS m/z:calu[M+4H]4+1235.1,[M+5H]5+988.3；found[M+4H]4+1235.7,[M+5H]5+988.6。
实施例22
理论相对分子质量为4936.5。ESI-MS m/z:calu[M+4H]4+1235.1,[M+5H]5+988.3；found[M+4H]4+1235.1,[M+5H]5+988.4。
实施例23
理论相对分子质量为5608.4。ESI-MS m/z:calu[M+4H]4+1403.1,[M+5H]5+1122.7；found[M+4H]4+1403.5,[M+5H]5+1122.9。
实施例24
理论相对分子质量为5608.4。ESI-MS m/z:calu[M+4H]4+1403.1,[M+5H]5+1122.7；found[M+4H]4+1403.2,[M+5H]5+1122.7。
实施例25
理论相对分子质量为4216.7。ESI-MS m/z:calu[M+4H]4+1055.2,[M+5H]5+844.3；found[M+4H]4+1055.6,[M+5H]5+844.6。
实施例26
理论相对分子质量为4216.7。ESI-MS m/z:calu[M+4H]4+1055.2,[M+5H]5+844.3；found[M+4H]4+1055.2,[M+5H]5+844.4。
实施例27
理论相对分子质量为4994.5。ESI-MS m/z:calu[M+4H]4+1249.6,[M+5H]5+999.9；found[M+4H]4+1249.9,[M+5H]5+1000.3。
实施例28
理论相对分子质量为4994.5。ESI-MS m/z:calu[M+4H]4+1249.6,[M+5H]5+999.9；found[M+4H]4+1250.1,[M+5H]5+1000.2。
实施例29
理论相对分子质量为5666.4。ESI-MS m/z:calu[M+4H]4+1417.6,[M+5H]5+1134.3；found[M+4H]4+1417.8,[M+5H]5+1134.6。
实施例30
理论相对分子质量为5666.4。ESI-MS m/z:calu[M+4H]4+1417.6,[M+5H]5+1134.3；found[M+4H]4+1418.0,[M+5H]5+1134.9。
实施例31
体外GLP-1受体激动实验
将编码人GLP-1受体的cDNA克隆至载体pcDNA3.0上，转染HEK293细胞，得到能稳定表达人GLP-1受体的HEK293细胞。细胞在DMEM-31053培养基中培养，实验2h前将HEK293细胞重新悬浮于生长培养基中并接种在96孔板中。将liraglutide，semaglutide和SEQ.ID NO:2-31用DMSO溶解后按照1pM-1000nM的浓度梯度稀释后加入96孔板中，然后在室温下孵育20分钟后使用cAMP试剂盒在Envision 2104酶标仪中测定生成的cAMP的量，分析数据，计算化合物的EC50值。
如表1所示，所有XenGLP-1类似物的受体激动活性都优于liraglutide和semaglutide，C末端经过修饰的XenGLP-1类似物的受体激动活性高于C末端未经修饰的XenGLP-1类似物，XenGLP-1类似物侧链脂肪链的长度与其受体激动活性成反比，脂肪链侧链中短链PEG片段的引入对XenGLP-1类似物的受体激动活性没有影响。
表1Liraglutide，semaglutide和XenGLP-1类似物的体外活性
实施例32
XenGLP-1类似物的体外血浆稳定性实验
大鼠眼球取血，血液装入含有肝素的离心管中，3000rpm离心10分钟，取上清血浆作为温孵血浆，利用LC-MS来检测化合物的响应信号。100uL的liraglutide， semaglutide及SEQ.ID NO:2-31溶液与100uL的血浆，涡旋混合后置入37℃水浴中，温孵96小时，在0，12，24，48，72，96h时间点取10uL，加入20uL 乙腈沉淀，14000rpm离心，取上清液进LC-MS，计算各个时间点的峰面积，做出衰减曲线，计算半衰期。如图1所示，liraglutide和semaglutide的半衰期分别为16.3及45.9h，而所有的XenGLP-1类似物的半衰期全部在60h以上，其中最长的半衰期已经超过96h。
实施例33
XenGLP-1类似物的体内急性降血糖活性
同时给予葡萄糖、受试化合物：10周龄雄性db/db小鼠，随机分组，每组6只。只给饮水，禁食过夜。一组按照小鼠体重每千克腹腔注射18mmol的葡萄糖溶液 (浓度20％)和生理盐水；其他组按照小鼠体重每千克腹腔注射18mmol的葡萄糖溶液和25nmol的liraglutide，semaglutide及SEQ.ID NO:2，SEQ.ID NO:8， SEQ.ID NO:14，SEQ.ID NO:20，SEQ.ID NO:22，SEQ.ID NO:24，SEQ.ID NO: 26，SEQ.ID NO:28，SEQ.ID NO:30溶液(10μmol/L)。在0，15，30，45，60 min用血糖仪测定血糖水平。如表1所示，修饰后的XenGLP-1类似物的降糖活性显著优于liraglutide和semaglutide，具有良好的应用前景，也说明脂肪酸化修饰并没有影响类似物的降糖活性。
表1Liraglutide，semaglutide及XenGLP-1类似物降血糖的效应
n＝6,
实施例34
XenGLP-1类似物的长效降糖实验
8周龄db/db糖尿病模型小鼠，适应性饲养一周，血糖仪测定小鼠的血糖值高于20mmol/L后，随机分组，每组六只。分为阳性对照组liraglutide和semaglutide (25nmol/kg)，阴性对照组生理盐水，化合物组SEQ.ID NO:2，SEQ.ID NO:8， SEQ.ID NO:14，SEQ.IDNO:20，SEQ.ID NO:22，SEQ.ID NO:24，SEQ.ID NO: 26，SEQ.ID NO:28，SEQ.ID NO:30(25nmol/kg)。小鼠自由饮水、饮食，0h给予化合物，在0，6，12，24，48，72h用血糖仪测定血糖，做出时间-血糖曲线。如图2所示，XenGLP-1类似物的长效降糖活性显著的优于liraglutide和 semaglutide，大部分XenGLP-1类似物的降糖时间都超过72h。
实施例35
XenGLP-1类似物的降低体重实验
9周龄db/db糖尿病模型小鼠，适应性饲养一周，随机分组，每组6只。小鼠每天给予阳性对照liraglutide和semaglutide(25nmol/kg)，阴性对照生理盐水，给药组每天给予SEQ.ID NO:2，SEQ.ID NO:8，SEQ.ID NO:14，SEQ.ID NO:20， SEQ.ID NO:22，SEQ.ID NO:24，SEQ.ID NO:26，SEQ.ID NO:28，SEQ.ID NO: 30(25nmol/kg)，治疗周期40天，每10天检测一次小鼠的体重。如图3所示， XenGLP-1类似物能显著降低小鼠的体重，它们的体重减轻作用显著优于阳性对照liraglutide和semaglutide，表明了XenGLP-1类似物具有良好的治疗糖尿病和减肥的药用前景。
[0001] 序列表
[0002] <110>江苏师范大学
[0003] <120>非洲爪蟾GLP-1类似物及其用途
[0004] <160>31
[0005] <170>SIPOSequenceListing 1.0
[0006] <210>1
[0007] <211>31
[0008] <212>PRT
[0009] <213>Artificial sequence
[0010] <220>
[0011] <221>VARIANT
[0012] <222>(2)..(2)
[0013] <223>第2位的Xaa是Ala，Gly或Aib
[0014] <220>
[0015] <221>VARIANT
[0016] <222>(20)..(20)
[0017] <223>第20位的Xaa是Lys(fatty acid analog)或Lys
[0018] <220>
[0019] <221>VARIANT
[0020] <222>(28)..(28)
[0021] <223>第28位的Xaa是Lys(fatty acid analog)或Lys
[0022] <220>
[0023] <221>VARIANT
[0024] <222>(30)..(30)
[0025] <223>第13位的Xaa是Lys(fatty acid analog)或Lys
[0026] <220>
[0027] <221>VARIANT
[0028] <222>(31)..(31)
[0029] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2，Pro SerSer Gly
[0030] Ala Pro Pro Pro Ser-OH，Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys LysLys Lys Lys-NH2，
[0031] Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys-OH，-OH或-NH2
[0032] <220>
[0033] <221>UNSURE
[0034] <222>(2)..(2)
[0035] <223>The'Xaa'at location 2 stands for Gln,Arg,Pro,or Leu.
[0036] <220>
[0037] <221>UNSURE
[0038] <222>(20)..(20)
[0039] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0040] <220>
[0041] <221>UNSURE
[0042] <222>(28)..(28)
[0043] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0044] <220>
[0045] <221>UNSURE
[0046] <222>(30)..(30)
[0047] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0048] <220>
[0049] <221>UNSURE
[0050] <222>(31)..(31)
[0051] <223>The'Xaa'at location 31 stands for Gln,Arg,Pro,or Leu.
[0052] <220>
[0053] <221>UNSURE
[0054] <222>(2)..(2)
[0055] <223>The'Xaa'at location 2 stands for Gln,Arg,Pro,or Leu.
[0056] <220>
[0057] <221>UNSURE
[0058] <222>(20)..(20)
[0059] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0060] <220>
[0061] <221>UNSURE
[0062] <222>(28)..(28)
[0063] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0064] <220>
[0065] <221>UNSURE
[0066] <222>(30)..(30)
[0067] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0068] <220>
[0069] <221>UNSURE
[0070] <222>(31)..(31)
[0071] <223>The'Xaa'at location 31 stands for Gln,Arg,Pro,or Leu.
[0072] <220>
[0073] <221>UNSURE
[0074] <222>(2)..(2)
[0075] <223>The'Xaa'at location 2 stands for Gln,Arg,Pro,or Leu.
[0076] <220>
[0077] <221>UNSURE
[0078] <222>(20)..(20)
[0079] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0080] <220>
[0081] <221>UNSURE
[0082] <222>(28)..(28)
[0083] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0084] <220>
[0085] <221>UNSURE
[0086] <222>(30)..(30)
[0087] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0088] <220>
[0089] <221>UNSURE
[0090] <222>(31)..(31)
[0091] <223>The'Xaa'at location 31 stands for Gln,Arg,Pro,or Leu.
[0092] <400>1
[0093] His Xaa Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0094] 1 5 10 15
[0095] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Xaa Gly Xaa Xaa
[0096] 20 25 30
[0097] <210>2
[0098] <211>30
[0099] <212>PRT
[0100] <213>Artificial sequence
[0101] <220>
[0102] <221>VARIANT
[0103] <222>(20)..(20)
[0104] <223>第20位的Xaa是Lys(fatty acid analog)
[0105] <220>
[0106] <221>UNSURE
[0107] <222>(20)..(20)
[0108] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0109] <220>
[0110] <221>UNSURE
[0111] <222>(20)..(20)
[0112] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0113] <220>
[0114] <221>UNSURE
[0115] <222>(20)..(20)
[0116] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0117] <400>2
[0118] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0119] 1 5 10 15
[0120] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
[0121] 20 25 30
[0122] <210>3
[0123] <211>30
[0124] <212>PRT
[0125] <213>Artificial sequence
[0126] <220>
[0127] <221>VARIANT
[0128] <222>(28)..(28)
[0129] <223>第28位的Xaa是Lys(fatty acid analog)
[0130] <220>
[0131] <221>UNSURE
[0132] <222>(28)..(28)
[0133] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0134] <220>
[0135] <221>UNSURE
[0136] <222>(28)..(28)
[0137] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0138] <220>
[0139] <221>UNSURE
[0140] <222>(28)..(28)
[0141] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0142] <400>3
[0143] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0144] 1 5 10 15
[0145] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
[0146] 20 25 30
[0147] <210>4
[0148] <211>30
[0149] <212>PRT
[0150] <213>Artificial sequence
[0151] <220>
[0152] <221>VARIANT
[0153] <222>(30)..(30)
[0154] <223>第30位的Xaa是Lys(fatty acid analog)
[0155] <220>
[0156] <221>UNSURE
[0157] <222>(30)..(30)
[0158] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0159] <220>
[0160] <221>UNSURE
[0161] <222>(30)..(30)
[0162] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0163] <220>
[0164] <221>UNSURE
[0165] <222>(30)..(30)
[0166] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0167] <400>4
[0168] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0169] 1 5 10 15
[0170] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa
[0171] 20 25 30
[0172] <210>5
[0173] <211>30
[0174] <212>PRT
[0175] <213>Artificial sequence
[0176] <220>
[0177] <221>VARIANT
[0178] <222>(20)..(20)
[0179] <223>第20位的Xaa是Lys(fatty acid analog)
[0180] <220>
[0181] <221>UNSURE
[0182] <222>(20)..(20)
[0183] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0184] <220>
[0185] <221>UNSURE
[0186] <222>(20)..(20)
[0187] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0188] <220>
[0189] <221>UNSURE
[0190] <222>(20)..(20)
[0191] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0192] <400>5
[0193] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0194] 1 5 10 15
[0195] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
[0196] 20 25 30
[0197] <210>6
[0198] <211>30
[0199] <212>PRT
[0200] <213>Artificial sequence
[0201] <220>
[0202] <221>VARIANT
[0203] <222>(28)..(28)
[0204] <223>第28位的Xaa是Lys(fatty acid analog)
[0205] <220>
[0206] <221>UNSURE
[0207] <222>(28)..(28)
[0208] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0209] <220>
[0210] <221>UNSURE
[0211] <222>(28)..(28)
[0212] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0213] <220>
[0214] <221>UNSURE
[0215] <222>(28)..(28)
[0216] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0217] <400>6
[0218] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0219] 1 5 10 15
[0220] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
[0221] 20 25 30
[0222] <210>7
[0223] <211>30
[0224] <212>PRT
[0225] <213>Artificial sequence
[0226] <220>
[0227] <221>VARIANT
[0228] <222>(30)..(30)
[0229] <223>第30位的Xaa是Lys(fatty acid analog)
[0230] <220>
[0231] <221>UNSURE
[0232] <222>(30)..(30)
[0233] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0234] <220>
[0235] <221>UNSURE
[0236] <222>(30)..(30)
[0237] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0238] <220>
[0239] <221>UNSURE
[0240] <222>(30)..(30)
[0241] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0242] <400>7
[0243] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0244] 1 5 10 15
[0245] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa
[0246] 20 25 30
[0247] <210>8
[0248] <211>39
[0249] <212>PRT
[0250] <213>Artificial sequence
[0251] <220>
[0252] <221>VARIANT
[0253] <222>(20)..(20)
[0254] <223>第20位的Xaa是Lys(fatty acid analog)
[0255] <220>
[0256] <221>VARIANT
[0257] <222>(31)..(31)
[0258] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0259] <220>
[0260] <221>UNSURE
[0261] <222>(20)..(20)
[0262] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0263] <220>
[0264] <221>UNSURE
[0265] <222>(20)..(20)
[0266] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0267] <220>
[0268] <221>UNSURE
[0269] <222>(20)..(20)
[0270] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0271] <400>8
[0272] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0273] 1 5 10 15
[0274] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0275] 20 25 30
[0276] Ser Gly Ala Pro Pro Pro Ser
[0277] 35
[0278] <210>9
[0279] <211>39
[0280] <212>PRT
[0281] <213>Artificial sequence
[0282] <220>
[0283] <221>VARIANT
[0284] <222>(28)..(28)
[0285] <223>第28位的Xaa是Lys(fatty acid analog)
[0286] <220>
[0287] <221>VARIANT
[0288] <222>(31)..(31)
[0289] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0290] <220>
[0291] <221>UNSURE
[0292] <222>(28)..(28)
[0293] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0294] <220>
[0295] <221>UNSURE
[0296] <222>(28)..(28)
[0297] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0298] <220>
[0299] <221>UNSURE
[0300] <222>(28)..(28)
[0301] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0302] <400>9
[0303] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0304] 1 5 10 15
[0305] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0306] 20 25 30
[0307] Ser Gly Ala Pro Pro Pro Ser
[0308] 35
[0309] <210>10
[0310] <211>39
[0311] <212>PRT
[0312] <213>Artificial sequence
[0313] <220>
[0314] <221>VARIANT
[0315] <222>(30)..(30)
[0316] <223>第30位的Xaa是Lys(fatty acid analog)
[0317] <220>
[0318] <221>VARIANT
[0319] <222>(31)..(31)
[0320] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0321] <220>
[0322] <221>UNSURE
[0323] <222>(30)..(30)
[0324] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0325] <220>
[0326] <221>UNSURE
[0327] <222>(30)..(30)
[0328] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0329] <220>
[0330] <221>UNSURE
[0331] <222>(30)..(30)
[0332] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0333] <400>10
[0334] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0335] 1 5 10 15
[0336] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
[0337] 20 25 30
[0338] Ser Gly Ala Pro Pro Pro Ser
[0339] 35
[0340] <210>11
[0341] <211>39
[0342] <212>PRT
[0343] <213>Artificial sequence
[0344] <220>
[0345] <221>VARIANT
[0346] <222>(20)..(20)
[0347] <223>第20位的Xaa是Lys(fatty acid analog)
[0348] <220>
[0349] <221>VARIANT
[0350] <222>(31)..(31)
[0351] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0352] <220>
[0353] <221>UNSURE
[0354] <222>(20)..(20)
[0355] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0356] <220>
[0357] <221>UNSURE
[0358] <222>(20)..(20)
[0359] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0360] <220>
[0361] <221>UNSURE
[0362] <222>(20)..(20)
[0363] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0364] <400>11
[0365] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0366] 1 5 10 15
[0367] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0368] 20 25 30
[0369] Ser Gly Ala Pro Pro Pro Ser
[0370] 35
[0371] <210>12
[0372] <211>39
[0373] <212>PRT
[0374] <213>Artificial sequence
[0375] <220>
[0376] <221>VARIANT
[0377] <222>(28)..(28)
[0378] <223>第28位的Xaa是Lys(fatty acid analog)
[0379] <220>
[0380] <221>VARIANT
[0381] <222>(31)..(31)
[0382] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0383] <220>
[0384] <221>UNSURE
[0385] <222>(28)..(28)
[0386] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0387] <220>
[0388] <221>UNSURE
[0389] <222>(28)..(28)
[0390] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0391] <220>
[0392] <221>UNSURE
[0393] <222>(28)..(28)
[0394] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0395] <400>12
[0396] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0397] 1 5 10 15
[0398] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0399] 20 25 30
[0400] Ser Gly Ala Pro Pro Pro Ser
[0401] 35
[0402] <210>13
[0403] <211>39
[0404] <212>PRT
[0405] <213>Artificial sequence
[0406] <220>
[0407] <221>VARIANT
[0408] <222>(30)..(30)
[0409] <223>第30位的Xaa是Lys(fatty acid analog)
[0410] <220>
[0411] <221>VARIANT
[0412] <222>(31)..(31)
[0413] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0414] <220>
[0415] <221>UNSURE
[0416] <222>(30)..(30)
[0417] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0418] <220>
[0419] <221>UNSURE
[0420] <222>(30)..(30)
[0421] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0422] <220>
[0423] <221>UNSURE
[0424] <222>(30)..(30)
[0425] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0426] <400>13
[0427] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0428] 1 5 10 15
[0429] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
[0430] 20 25 30
[0431] Ser Gly Ala Pro Pro Pro Ser
[0432] 35
[0433] <210>14
[0434] <211>44
[0435] <212>PRT
[0436] <213>Artificial sequence
[0437] <220>
[0438] <221>VARIANT
[0439] <222>(20)..(20)
[0440] <223>第20位的Xaa是Lys(fatty acid analog)
[0441] <220>
[0442] <221>VARIANT
[0443] <222>(31)..(31)
[0444] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0445] <220>
[0446] <221>UNSURE
[0447] <222>(20)..(20)
[0448] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0449] <220>
[0450] <221>UNSURE
[0451] <222>(20)..(20)
[0452] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0453] <220>
[0454] <221>UNSURE
[0455] <222>(20)..(20)
[0456] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0457] <400>14
[0458] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0459] 1 5 10 15
[0460] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0461] 20 25 30
[0462] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0463] 35 40
[0464] <210>15
[0465] <211>44
[0466] <212>PRT
[0467] <213>Artificial sequence
[0468] <220>
[0469] <221>VARIANT
[0470] <222>(28)..(28)
[0471] <223>第28位的Xaa是Lys(fatty acid analog)
[0472] <220>
[0473] <221>VARIANT
[0474] <222>(31)..(31)
[0475] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0476] <220>
[0477] <221>UNSURE
[0478] <222>(28)..(28)
[0479] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0480] <220>
[0481] <221>UNSURE
[0482] <222>(28)..(28)
[0483] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0484] <220>
[0485] <221>UNSURE
[0486] <222>(28)..(28)
[0487] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0488] <400>15
[0489] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0490] 1 5 10 15
[0491] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0492] 20 25 30
[0493] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0494] 35 40
[0495] <210>16
[0496] <211>44
[0497] <212>PRT
[0498] <213>Artificial sequence
[0499] <220>
[0500] <221>VARIANT
[0501] <222>(30)..(30)
[0502] <223>第30位的Xaa是Lys(fatty acid analog)
[0503] <220>
[0504] <221>VARIANT
[0505] <222>(31)..(31)
[0506] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0507] <220>
[0508] <221>UNSURE
[0509] <222>(30)..(30)
[0510] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0511] <220>
[0512] <221>UNSURE
[0513] <222>(30)..(30)
[0514] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0515] <220>
[0516] <221>UNSURE
[0517] <222>(30)..(30)
[0518] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0519] <400>16
[0520] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0521] 1 5 10 15
[0522] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
[0523] 20 25 30
[0524] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0525] 35 40
[0526] <210>17
[0527] <211>44
[0528] <212>PRT
[0529] <213>Artificial sequence
[0530] <220>
[0531] <221>VARIANT
[0532] <222>(20)..(20)
[0533] <223>第20位的Xaa是Lys(fatty acid analog)
[0534] <220>
[0535] <221>VARIANT
[0536] <222>(31)..(31)
[0537] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0538] <220>
[0539] <221>UNSURE
[0540] <222>(20)..(20)
[0541] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0542] <220>
[0543] <221>UNSURE
[0544] <222>(20)..(20)
[0545] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0546] <220>
[0547] <221>UNSURE
[0548] <222>(20)..(20)
[0549] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0550] <400>17
[0551] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0552] 1 5 10 15
[0553] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0554] 20 25 30
[0555] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0556] 35 40
[0557] <210>18
[0558] <211>44
[0559] <212>PRT
[0560] <213>Artificial sequence
[0561] <220>
[0562] <221>VARIANT
[0563] <222>(28)..(28)
[0564] <223>第28位的Xaa是Lys(fatty acid analog)
[0565] <220>
[0566] <221>VARIANT
[0567] <222>(31)..(31)
[0568] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0569] <220>
[0570] <221>UNSURE
[0571] <222>(28)..(28)
[0572] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0573] <220>
[0574] <221>UNSURE
[0575] <222>(28)..(28)
[0576] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0577] <220>
[0578] <221>UNSURE
[0579] <222>(28)..(28)
[0580] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0581] <400>18
[0582] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0583] 1 5 10 15
[0584] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0585] 20 25 30
[0586] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0587] 35 40
[0588] <210>19
[0589] <211>44
[0590] <212>PRT
[0591] <213>Artificial sequence
[0592] <220>
[0593] <221>VARIANT
[0594] <222>(30)..(30)
[0595] <223>第30位的Xaa是Lys(fatty acid analog)
[0596] <220>
[0597] <221>VARIANT
[0598] <222>(31)..(31)
[0599] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0600] <220>
[0601] <221>UNSURE
[0602] <222>(30)..(30)
[0603] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0604] <220>
[0605] <221>UNSURE
[0606] <222>(30)..(30)
[0607] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0608] <220>
[0609] <221>UNSURE
[0610] <222>(30)..(30)
[0611] <223>The'Xaa'at location 30 stands for Gln,Arg,Pro,or Leu.
[0612] <400>19
[0613] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0614] 1 5 10 15
[0615] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Xaa Pro Ser
[0616] 20 25 30
[0617] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0618] 35 40
[0619] <210>20
[0620] <211>30
[0621] <212>PRT
[0622] <213>Artificial sequence
[0623] <220>
[0624] <221>VARIANT
[0625] <222>(20)..(20)
[0626] <223>第20位的Xaa是Lys(fatty acid analog)
[0627] <220>
[0628] <221>UNSURE
[0629] <222>(20)..(20)
[0630] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0631] <220>
[0632] <221>UNSURE
[0633] <222>(20)..(20)
[0634] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0635] <220>
[0636] <221>UNSURE
[0637] <222>(20)..(20)
[0638] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0639] <400>20
[0640] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0641] 1 5 10 15
[0642] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
[0643] 20 25 30
[0644] <210>21
[0645] <211>30
[0646] <212>PRT
[0647] <213>Artificial sequence
[0648] <220>
[0649] <221>VARIANT
[0650] <222>(28)..(28)
[0651] <223>第28位的Xaa是Lys(fatty acid analog)
[0652] <220>
[0653] <221>UNSURE
[0654] <222>(28)..(28)
[0655] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0656] <220>
[0657] <221>UNSURE
[0658] <222>(28)..(28)
[0659] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0660] <220>
[0661] <221>UNSURE
[0662] <222>(28)..(28)
[0663] <223>The'Xaa'atlocation 28 stands for Gln,Arg,Pro,or Leu.
[0664] <400>21
[0665] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0666] 1 5 10 15
[0667] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
[0668] 20 25 30
[0669] <210>22
[0670] <211>39
[0671] <212>PRT
[0672] <213>Artificial sequence
[0673] <220>
[0674] <221>VARIANT
[0675] <222>(20)..(20)
[0676] <223>第20位的Xaa是Lys(fatty acid analog)
[0677] <220>
[0678] <221>VARIANT
[0679] <222>(31)..(31)
[0680] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0681] <220>
[0682] <221>UNSURE
[0683] <222>(20)..(20)
[0684] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0685] <220>
[0686] <221>UNSURE
[0687] <222>(20)..(20)
[0688] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0689] <220>
[0690] <221>UNSURE
[0691] <222>(20)..(20)
[0692] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0693] <400>22
[0694] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0695] 1 5 10 15
[0696] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0697] 20 25 30
[0698] Ser Gly Ala Pro Pro Pro Ser
[0699] 35
[0700] <210>23
[0701] <211>39
[0702] <212>PRT
[0703] <213>Artificial sequence
[0704] <220>
[0705] <221>VARIANT
[0706] <222>(28)..(28)
[0707] <223>第28位的Xaa是Lys(fatty acid analog)
[0708] <220>
[0709] <221>VARIANT
[0710] <222>(31)..(31)
[0711] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0712] <220>
[0713] <221>UNSURE
[0714] <222>(28)..(28)
[0715] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0716] <220>
[0717] <221>UNSURE
[0718] <222>(28)..(28)
[0719] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0720] <220>
[0721] <221>UNSURE
[0722] <222>(28)..(28)
[0723] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0724] <400>23
[0725] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0726] 1 5 10 15
[0727] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0728] 20 25 30
[0729] Ser Gly Ala Pro Pro Pro Ser
[0730] 35
[0731] <210>24
[0732] <211>44
[0733] <212>PRT
[0734] <213>Artificial sequence
[0735] <220>
[0736] <221>VARIANT
[0737] <222>(20)..(20)
[0738] <223>第20位的Xaa是Lys(fatty acid analog)
[0739] <220>
[0740] <221>VARIANT
[0741] <222>(31)..(31)
[0742] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0743] <220>
[0744] <221>UNSURE
[0745] <222>(20)..(20)
[0746] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0747] <220>
[0748] <221>UNSURE
[0749] <222>(20)..(20)
[0750] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0751] <220>
[0752] <221>UNSURE
[0753] <222>(20)..(20)
[0754] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0755] <400>24
[0756] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0757] 1 5 10 15
[0758] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0759] 20 25 30
[0760] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0761] 35 40
[0762] <210>25
[0763] <211>44
[0764] <212>PRT
[0765] <213>Artificial sequence
[0766] <220>
[0767] <221>VARIANT
[0768] <222>(28)..(28)
[0769] <223>第28位的Xaa是Lys(fatty acid analog)
[0770] <220>
[0771] <221>VARIANT
[0772] <222>(31)..(31)
[0773] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0774] <220>
[0775] <221>UNSURE
[0776] <222>(28)..(28)
[0777] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0778] <220>
[0779] <221>UNSURE
[0780] <222>(28)..(28)
[0781] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0782] <220>
[0783] <221>UNSURE
[0784] <222>(28)..(28)
[0785] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0786] <400>25
[0787] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0788] 1 5 10 15
[0789] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0790] 20 25 30
[0791] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0792] 35 40
[0793] <210>26
[0794] <211>30
[0795] <212>PRT
[0796] <213>Artificial sequence
[0797] <220>
[0798] <221>VARIANT
[0799] <222>(20)..(20)
[0800] <223>第20位的Xaa是Lys(fatty acid analog)
[0801] <220>
[0802] <221>UNSURE
[0803] <222>(20)..(20)
[0804] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0805] <220>
[0806] <221>UNSURE
[0807] <222>(20)..(20)
[0808] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0809] <220>
[0810] <221>UNSURE
[0811] <222>(20)..(20)
[0812] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0813] <400>26
[0814] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0815] 1 5 10 15
[0816] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys
[0817] 20 25 30
[0818] <210>27
[0819] <211>30
[0820] <212>PRT
[0821] <213>Artificial sequence
[0822] <220>
[0823] <221>VARIANT
[0824] <222>(28)..(28)
[0825] <223>第28位的Xaa是Lys(fatty acid analog)
[0826] <220>
[0827] <221>UNSURE
[0828] <222>(28)..(28)
[0829] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0830] <220>
[0831] <221>UNSURE
[0832] <222>(28)..(28)
[0833] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0834] <220>
[0835] <221>UNSURE
[0836] <222>(28)..(28)
[0837] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0838] <400>27
[0839] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0840] 1 5 10 15
[0841] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys
[0842] 20 25 30
[0843] <210>28
[0844] <211>39
[0845] <212>PRT
[0846] <213>Artificial sequence
[0847] <220>
[0848] <221>VARIANT
[0849] <222>(20)..(20)
[0850] <223>第20位的Xaa是Lys(fatty acid analog)
[0851] <220>
[0852] <221>VARIANT
[0853] <222>(31)..(31)
[0854] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0855] <220>
[0856] <221>UNSURE
[0857] <222>(20)..(20)
[0858] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0859] <220>
[0860] <221>UNSURE
[0861] <222>(20)..(20)
[0862] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0863] <220>
[0864] <221>UNSURE
[0865] <222>(20)..(20)
[0866] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0867] <400>28
[0868] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0869] 1 5 10 15
[0870] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0871] 20 25 30
[0872] Ser Gly Ala Pro Pro Pro Ser
[0873] 35
[0874] <210>29
[0875] <211>39
[0876] <212>PRT
[0877] <213>Artificial sequence
[0878] <220>
[0879] <221>VARIANT
[0880] <222>(28)..(28)
[0881] <223>第28位的Xaa是Lys(fatty acid analog)
[0882] <220>
[0883] <221>VARIANT
[0884] <222>(31)..(31)
[0885] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2
[0886] <220>
[0887] <221>UNSURE
[0888] <222>(28)..(28)
[0889] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0890] <220>
[0891] <221>UNSURE
[0892] <222>(28)..(28)
[0893] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0894] <220>
[0895] <221>UNSURE
[0896] <222>(28)..(28)
[0897] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0898] <400>29
[0899] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0900] 1 5 10 15
[0901] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0902] 20 25 30
[0903] Ser Gly Ala Pro Pro Pro Ser
[0904] 35
[0905] <210>30
[0906] <211>44
[0907] <212>PRT
[0908] <213>Artificial sequence
[0909] <220>
[0910] <221>VARIANT
[0911] <222>(20)..(20)
[0912] <223>第20位的Xaa是Lys(fatty acid analog)
[0913] <220>
[0914] <221>VARIANT
[0915] <222>(31)..(31)
[0916] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0917] <220>
[0918] <221>UNSURE
[0919] <222>(20)..(20)
[0920] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0921] <220>
[0922] <221>UNSURE
[0923] <222>(20)..(20)
[0924] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0925] <220>
[0926] <221>UNSURE
[0927] <222>(20)..(20)
[0928] <223>The'Xaa'at location 20 stands for Gln,Arg,Pro,or Leu.
[0929] <400>30
[0930] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0931] 1 5 10 15
[0932] Glu Ala Ala Xaa Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser
[0933] 20 25 30
[0934] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0935] 35 40
[0936] <210>31
[0937] <211>44
[0938] <212>PRT
[0939] <213>Artificial sequence
[0940] <220>
[0941] <221>VARIANT
[0942] <222>(28)..(28)
[0943] <223>第28位的Xaa是Lys(fatty acid analog)
[0944] <220>
[0945] <221>VARIANT
[0946] <222>(31)..(31)
[0947] <223>第31位的Xaa是Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys LysLys Lys-NH2
[0948] <220>
[0949] <221>UNSURE
[0950] <222>(28)..(28)
[0951] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0952] <220>
[0953] <221>UNSURE
[0954] <222>(28)..(28)
[0955] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0956] <220>
[0957] <221>UNSURE
[0958] <222>(28)..(28)
[0959] <223>The'Xaa'at location 28 stands for Gln,Arg,Pro,or Leu.
[0960] <400>31
[0961] His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Leu Glu Glu
[0962] 1 5 10 15
[0963] Glu Ala Ala Lys Glu Phe Ile Glu Trp Leu Ile Xaa Gly Lys Pro Ser
[0964] 20 25 30
[0965] Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys
[0966] 35 40
Claims (7)
1.一种含有式Ⅰ(SEQ.ID NO：1)结构的非洲爪蟾胰高血糖素样肽-1(XenGLP-1)类似物，其序列为：
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Xaa2-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Xaa3-Gly-Xaa4-Xaa5(SEQ.ID NO:1)
其中：
Xaa1:Ala，Gly或Aib；
Xaa2:Lys(fatty acid analog)或Lys；
Xaa3:Lys(fatty acid analog)或Lys；
Xaa4:Lys(fatty acid analog)或Lys；
Xaa5:Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2，Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-OH，-OH或-NH2；
前提是所述序列不是His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-NH2,His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-OH，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH，His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2或His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Glu-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-OH；
以及该类似物所成的可药用的盐、溶剂化物、螯合物或非共价复合物，基于该类似物基础上的药物前体，或上述形式类似物的任意混合物。
2.根据权利要求1所述的类似物，其中Lys(fatty acid analog)选自
这里：n选自12～20。
3.根据权利要求2所述，其中优选的Lys(fatty acid analog)结构为
4.根据权利要求1所述的非洲爪蟾胰高血糖素样肽-1(XenGLP-1)类似物，优选的序列为：
5.一种药物组合物，包括治疗有效量的权利要求1中所述的非洲爪蟾胰高血糖素样肽-1(XenGLP-1)类似物或其药学上可接受的盐、溶剂化物、螯合物或非共价复合物，基于该类似物基础上的药物前体，或上述形式类似物的任意混合物，和一种或者多种药学上可接受的载体、稀释剂或赋形剂。
6.权利要求1中所述的非洲爪蟾胰高血糖素样肽-1(XenGLP-1)类似物或其药学上可接受的盐或权利要求5中所述的药物组合物在药物中的应用。
7.权利要求6中所述的应用，包括所述类似物或药物组合物在制备治疗下述至少一种疾病的药物中的应用，所述疾病包括2型糖尿病、糖耐量受损、1型糖尿病、肥胖、高血压、代谢综合征、血脂异常、认知障碍、动脉粥样硬化、心肌梗塞、冠状动脉心脏病、心血管疾病、中风、炎性肠道综合征或消化不良。
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| CN109762059B (zh) * | 2019-03-28 | 2021-01-12 | 清紫生物科技（深圳）有限公司 | 一种新型胰高血糖素类似物及其应用 |
| CN112608378A (zh) * | 2020-12-09 | 2021-04-06 | 江苏师范大学 | 一类glp-1/胆囊收缩素-1受体双重激动剂及其应用 |
| CN112608378B (zh) * | 2020-12-09 | 2023-09-08 | 江苏师范大学 | 一类glp-1/胆囊收缩素-1受体双重激动剂及其应用 |
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