CN113265007B - 一种治疗代谢疾病的融合蛋白及其制备方法和应用 - Google Patents
一种治疗代谢疾病的融合蛋白及其制备方法和应用 Download PDFInfo
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- Peptides Or Proteins (AREA)
Abstract
本发明属于医药技术领域，涉及一种治疗代谢疾病的融合蛋白及其制备方法和应用，所述融合蛋白的通式为R1‑L‑R2或R2‑L‑R1；其中，R1为FGF21蛋白、FGF21蛋白类似物或具有FGF21蛋白生物学功能的类似肽，R2为GIP、突变型GIP或具有GIP生物学功能的类似肽，L为连接肽。本发明的融合蛋白作为一种治疗药物或者药物组合物，可用于高血糖和高血脂相关联的疾病如糖尿病、肥胖、脂肪性肝炎或心血管疾病的治疗，治疗效果显著优于原始FGF21及GIP。
Description
技术领域
本发明属于医药技术领域，涉及一种治疗代谢疾病的融合蛋白及其制备方法和应用。
背景技术
成纤维细胞生长因子(FGF)21属于FGF家族中一名新成员，FGF21基因主要在肝脏和脂肪中表达，FGF21在体外能够促进HepG2细胞和3T3-L1脂肪细胞消耗葡萄糖，在动物体内具有降低血糖和甘油三酯等功能，并且不会产生低血糖和引起肿瘤发生等副作用(Kharitonenkov A,et al.FGF21 as a novel metabolic regulator.J ClinInvest2005；115:1627–35.Kharitonenkov A,et al.The metabolic state ofdiabeticmonkeys is regulated by fibroblast growth factor-21.Endocrinology2007；148:774–81)。FGF21安全、有效以及不依赖胰岛素调节生物体内血糖水平的特点，使其有望成为治疗II型糖尿病的新型药物。但是多个临床试验发现FGF21类似物在糖尿病患者中并没有显著改善血糖的作用，这可能跟这些公司设计的FGF21类似物的活性和体内稳定性有关，所以对野生型FGF21进行更有效的改造和修饰逐渐成为近年来研究的热点。
抑胃肽(gastric inhibitory polypeptide,GIP)，或称葡萄糖依赖性胰岛素释放肽(GIP)是由小肠粘膜的K细胞所产生的一类激素，其可以抑制胃酸分泌；抑制胃蛋白酶原分泌；刺激胰岛素释放；抑制胃的蠕动和排空；刺激小肠液的分泌；刺激胰高血糖素的分泌。
FGF21能够分解脂肪，降低体重，改善脂质代谢，但无降低血糖的功能；GIP虽然可以促进胰岛素分泌，但是也可刺激胰高血糖素增加，若将GIP突变，使其保留刺激胰岛素分泌功能，新型GIP将与FGF21在生物活性方面显示出的相辅相成的作用。两者通过不同的靶细胞上的相应受体或相同靶细胞上的不同受体而发挥调节血糖的作用。若二者的功能可以有效结合，既能控制血糖，又能分解脂肪，降低体重。对于糖尿病、肥胖的治疗，双重功能比单纯的FGF21类似物具有显著的优势。
发明内容
本发明旨在提供一种融合蛋白，具有FGF21和GIP两者的生物活性，该融合蛋白作为一种治疗药物或者药物组合物，可用于高血糖和高血脂相关联的疾病如糖尿病、肥胖、脂肪性肝炎或心血管疾病的治疗。
按照本发明的技术方案，所述融合蛋白，通式为R1-L-R2或R2-L-R1；其中，R1为FGF21蛋白、FGF21蛋白类似物或具有FGF21蛋白生物学功能的类似肽，R2为GIP、突变型GIP或具有GIP生物学功能的类似肽，L为连接肽。
进一步的，所述FGF21蛋白类似物的氨基酸序列如SEQ ID NO：1或SEQ ID NO：2所示，或者是将SEQ ID NO：1或SEQ ID NO：2的氨基酸序列经过一个或几个氨基酸残基的取代、缺失。
进一步的，所述突变型GIP的氨基酸序列如SEQ ID NO：3或SEQ ID NO：4所示，或者是将SEQ ID NO：3或SEQ ID NO：4的氨基酸序列经过一个或几个氨基酸残基的取代、缺失。具有GIP生物学功能的类似肽可以为与SEQ ID No：3-4具有40％以上同源性、保留了GIP生物学作用的类似肽。
进一步的，所述连接肽由0-30个氨基酸组成。
优选的，FGF21蛋白的氨基酸序列如SEQ ID NO：1或SEQ ID NO：2所示，GIP的氨基酸序列如SEQ ID NO：3所示，连接肽为0个氨基酸，FGF21蛋白位于融合蛋白的C端。
进一步的，所述连接肽选自通式a-d中的一种或多种，
a：(Gly-Gly-Gly-Gly-Ser)n-(Ser)m，n为0-5中任一整数，m为0或1；
b：(Gly-Gly-Gly-Gly-Ser)n'-(Ser-Pro)m'，n'为0-5中任一整数，m'为0或1；
c：(Pro-Glu-Ala-Pro-Thr-Asp)n”，n”为0-5中任一整数；
d：(Ser-Ser-Ser-Ser-Gly)n”'-(Ser-Pro)m”，n”'为0-5中任一整数，m”为0或1；
进一步的，所述融合蛋白还包括药学上可接受的半衰期延长方式的修饰，所述的修饰为聚合物修饰、非结构化肽链修饰、弹性蛋白样多肽修饰、血清蛋白修饰、血清蛋白结合分子修饰、抗体修饰、免疫球蛋白修饰、免疫球蛋白的Fc区/域修饰和免疫球蛋白结合域修饰中的一种或多种。
本发明的第二方面提供了编码上述任一项所述融合蛋白的基因。
本发明的第三方面提供了携带上述基因的载体。
本发明的第四方面提供了含有上述载体的微生物细胞。
本发明的第五方面提供了上述融合蛋白的制备方法，包括以下步骤：
S1：在上述的微生物细胞中表达所述融合蛋白；
S2：分离、纯化所述融合蛋白。
本发明的第六方面提供了一种治疗代谢疾病的药物和/或药物组合物，含有上述融合蛋白，所述治疗代谢疾病包括抑制体重增加、降低血脂和血糖、提高胰岛素敏感性、降低肝脏重量和肝脏甘油三酯的含量、修复肝脏损伤、抑制炎症因子的表达、改善非酒精性脂肪性肝炎、改善动脉粥样硬化、改善肝损伤、改善肝硬化及肝癌、改善原发性胆汁性胆管炎和改善原发性硬化性胆管炎中的一种或多种。
进一步的，还包括药学上可接受的载体、赋形剂和稀释剂中的一种或多种。
进一步的，所述药物和/或药物组合物的给药途径包括口服、腹腔注射、皮下注射、静脉注射和肌肉注射中的一种或多种。
本发明的第六方面提供了上述融合蛋白、药物和/或药物组合物在治疗代谢疾病的药物中的应用，所述代谢疾病为糖尿病、肥胖、肝炎和肝炎相关疾病中的一种或多种。
进一步的，所述融合蛋白的剂量为1-100mg/kg。
本发明的技术方案相比现有技术具有以下优点：
(1)本发明的新型双靶点融合蛋白与原始FGF21类似物相比具有更长效、更稳定、更好的治疗胖症，超重，代谢综合征，糖尿病，高血糖症，血脂异常，非酒精性脂肪性肝炎(NASH)、动脉粥样硬化、肝损伤、肝硬化、肝癌、原发性胆汁性胆管炎(PBC)及原发性硬化性胆管炎(PSC)的功效；
(2)本发明的新型双靶点融合蛋白治疗过程中均未出现GIP治疗过程引起肠胃不适及饮食下降的副作用，对机体正常生命活动影响较小。
附图说明
图1是4种蛋白对db/db小鼠体重和饮食的影响图；
图2是4种蛋白对db/db小鼠血脂的影响图；
图3是4种蛋白对db/db小鼠糖尿病相关指标的影响图；
图4是4种蛋白对NASH模型小鼠脂肪性肝炎及肝纤维化等相关指标的影响。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实验动物及饲养：db/db小鼠购于上海斯莱克公司。饲养于江南大无锡医学院动物中心，每12小时交替照明，温度20±2℃。
其他药品为国产分析纯。
实施例1：重组蛋白的构建、表达及纯化
(1)GIP-FGF21-1及GIP-FGF21-2表达载体的构建
根据计算机模拟替换及大肠杆菌密码子偏好性，设计出2种新型融合蛋白基因，其氨基酸序列分别如序列表中GIP-FGF21-1(SEQ ID NO：5所示)、GIP-FGF21-2(SEQ ID NO：6所示)所示。将这2种基因送至上海捷瑞生物公司合成，同时在各基因两端设计NdeI与BamHI两酶切位点。将2种合成的含有各自目的基因片段的载体和pET30a(+)分别用NdeI与BamHI双酶切，酶切完毕后，胶回收各自需要的目标片段。使用T4DNA连接酶将4种目的片段分别与原核表达载体pET30a(+)连接，连接反应体系为10μL，混匀，4℃连接过夜，然后各自转化至大肠杆菌DH5α中。挑取阳性克隆，经过酶切鉴定后，即分别构建得到2种重组质粒pET30a-GIP-FGF21-1、pET30a-GIP-FGF21-2。
(2)蛋白的表达及纯化
将含有正确序列的重组质粒pET30a-GIP-FGF21-1、pET30a-GIP-FGF21-2转化至表达菌株Rosseta(DE3)感受态细胞中。转化后的单菌落分别接种至20mL含Kan(50μg/mL)的LB培养基中，37℃培养8h，以体积比为1:100接种于另一20mL含Kan(50μg/mL)的LB培养基中，37℃培养，当A600在0.35左右时，加入IPTG至终浓度为0.25mmol/L进行诱导，诱导温度为30℃，5h后收获菌体，用Lysis buffer(20mmol/LTris，150mmol/LNaCl，pH8.0)重悬菌体，破碎菌体后离心，分别取上清和沉淀进行12wt％SDS-PAGE电泳分析。结果显示GIP-FGF21-1、GIP-FGF21-2蛋白在大肠杆菌中表达量显著增加，目标蛋白大部分以包涵体形式存在。
收集大量诱导后的菌体，向菌体中加入溶菌酶(1mg/mL)，冰上放置30min，超声波细胞破碎菌体细胞(工作1s，间隔1s，4min/次，共3次循环)。菌体破碎彻底后，利用QuixStand预处理系统(750kD超滤中空纤维柱)处理细胞破碎液，富集包涵体，弃去膜透过端液体。当总体积约为60mL时，加入100mLwashbuffer(20mmol/LTris，2mol/LUrea，150mmol/LNaCl，pH8.0)洗涤包涵体。当溶液体积为50mL，再向其中加入洗涤液100mL，重复上述实验4次。洗涤完毕后，当溶液体积为50mL，关闭透过端，向洗涤后的包涵体中加入150mL的变性液(20mmol/LTris，10mol/LUrea，150mmol/LNaCl，pH8.0)，循环变性2小时。打开透过端，膜透过端收集液即为mFGF21变性液。用5KD中空纤维柱对变性后的mFGF21进行浓缩，至体积80mL后进行复性，将装有复性液(20mmol/LTris，50mmol/LNaCl，pH8.0)的容器用胶皮管与中空纤维柱的储液器连接。储液器密封后，透过端流出液体后，由于储存器中产生负压，使复性液以一定的速度滴加至变性液中，缓慢匀速复性。当加入复性液体积为变性液6倍时，即复性完毕，8000rpm/min，4℃离心20min，收集上清。复性上清液经AKTApurifier100系统，与5倍柱体积IEXbufferA(20mmol/LTris、10mmol/LNaCl，pH8.0)平衡好的CaptoQ柱(装于XK16/20空柱，柱高10cm，流速300cm/h)完全结合后，用3-4倍柱体积IEXbufferA冲洗；当紫外曲线达到稳定的基线时，利用IEXbufferA和IEXbufferB(20mmol/LTris，1mol/LNaCl，pH8.0)混合液洗脱，15wt％和100wt％IEXbufferB液冲洗杂蛋白，18.5wt％-19wt％IEXbufferB液洗脱目标蛋白，收集各洗脱峰，并进行15wt％SDSPAGE电泳分析。结果显示纯化后蛋白纯度在95％以上。
实施例2：重组蛋白对体重、饮食、血脂及糖尿病相关指标的影响
按照实施例1的方法制备FGF21(SEQ ID NO：7所示)，GIP-1(SEQ ID NO：3所示)，GIP-FGF21-1、GIP-FGF21-2这4种蛋白。
取SPF级8周龄雄性db/db小鼠50只，预饲养1周后称重，次日禁食不禁水6h，尾静脉取血测定小鼠的空腹血糖，剔除体重异常，筛选血糖及体重值相对接近均值的成模小鼠30只，随机分为生理盐水注射组(Saline)、FGF21组、GIP-1组、GIP-FGF21-1组、GIP-FGF21-2组，每组6只。于每天早上8点半左右给予实验组相应的受试物一次，腹腔注射，剂量2mg/kg，生理盐水组注射相同体积的生理盐水，连续给药8周。实验过程中自由饮食、饮水。期间监测小鼠饮食和体重状况。给药8周后，各实验组小鼠处死(前夜禁食)，眼球取血测定实验小鼠血糖、甘油三脂(TG)、总胆固醇(TC)水平。所得实验数据进行统计学分析。
实验检测数据如图1，结果表明，相对于生理盐水对照组，FGF21蛋白和GIP-1及2种新型蛋白GIP-FGF21-1、GIP-FGF21-2均可显著降低小鼠体重，但GIP-1蛋白注射后可显著降低小鼠饮食，抑制其食欲，而相对于GIP-1，2种新型蛋白GIP-FGF21-1、GIP-FGF21-2给药后不仅能更为强劲和显著的抑制体重外，且并不影响小鼠进食。
给药8周后，各实验组小鼠血清血脂水平结果如图2所示，相对于生理盐水组，4种FGF21、GIP-1、GIP-FGF21-1、GIP-FGF21-2注射后均可显著降低血清中TG、TC的含量，但GIP-FGF21-1、GIP-FGF21-2的治疗效果要优于原始GIP-1及FGF21。
给药8周后，各实验组小鼠空腹血糖及胰岛素敏感性、糖耐量结果如图3所示，相对于生理盐水组，4种FGF21、GIP-1、GIP-FGF21-1、GIP-FGF21-2注射后均可显著改善血糖及胰岛素抵抗，但GIP-FGF21-1、GIP-FGF21-2的治疗效果要优于原始GIP-1及FGF21。
实施例3：重组蛋白对非酒精性脂肪性肝炎(NASH)相关指标的影响
按照实施例1的方法制备FGF21，GIP-1，GIP-FGF21-1、GIP-FGF21-2这4种蛋白。取SPF级8周龄雄性C57BL/6小鼠60只，预饲养1周后喂食蛋氨酸胆碱缺失MCD饲料，喂食8周后，剔除体重异常，筛选血糖及体重值相对接近均值的成模小鼠30只，随机分为生理盐水注射组(Saline)、FGF21组、GIP-1组、GIP-FGF21-1组、GIP-FGF21-2组，每组6只。于每天早上8点半左右给予实验组相应的受试物一次，腹腔注射，剂量2mg/kg，生理盐水组注射相同体积的生理盐水，连续给药8周。实验过程中自由饮食、饮水。给药8周后，各实验组小鼠处死(前夜禁食)，测定实验小鼠肝脏甘油三脂(TG)、碱性磷酸酶(ALP)、谷丙转氨酶(ALT)水平并进行组织切片染色和炎症指标检测。所得实验数据进行统计学分析。
实验检测数据如图4所示，图4A结果表明，相对于生理盐水对照组(Saline)，FGF21、GIP-1、GIP-FGF21-1、GIP-FGF21-2均可显著降低小鼠肝脏重量和肝脏甘油三酯(TG)含量，但GIP-FGF21-1、GIP-FGF21-2的治疗效果要优于原始GIP-1及FGF21。图4B转氨酶结果进一步显示4种新型蛋白GIP-FGF21-1、GIP-FGF21-2对肝脏损伤的保护功能显著优于原始FGF21及GIP-1。此外，HE染色结果直接显示出GIP-FGF21-1、GIP-FGF21-2注射后可显著降低肝脏脂肪空泡，显微镜下几乎观察不到空泡，而FGF21、GIP-1治疗后还存在部分脂肪空泡(图4C)。图4D是天狼星红染色结果，用以观察肝脏胶原纤维沉积情况，反应肝脏纤维化，结果显示突变改造后的2种新型蛋白GIP-FGF21-1、GIP-FGF21-2均可逆转肝脏纤维化，而FGF21、GIP-1治疗会还存在部分纤维化状态，表明改造后的重组蛋白对肝脏纤维化的逆转效果显著优于原始蛋白。通过上述多项指标检测发现融合改造后的2种新型蛋白GIP-FGF21-1、GIP-FGF21-2针对NASH和肝脏损伤的治疗效果显著优于原始序列。
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
SEQUENCE LISTING
<110> 江南大学
<120> 一种治疗代谢疾病的融合蛋白及其制备方法和应用
<130> 1
<160> 7
<170> PatentIn version 3.3
<210> 1
<211> 209
<212> PRT
<213> （人工序列）
<400> 1
Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser Val
1 5 10 15
Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro Asp
20 25 30
Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu
35 40 45
Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu
50 55 60
Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu
65 70 75 80
Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys
85 90 95
Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser
100 105 110
Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu
115 120 125
Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His
130 135 140
Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro
145 150 155 160
Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro
165 170 175
Pro Gly Ile Leu Ala Pro Gln Pro Leu Glu Thr Asp Ser Met Asp Pro
180 185 190
Phe Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu
195 200 205
Lys
<210> 2
<211> 178
<212> PRT
<213> （人工序列）
<400> 2
Ala Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg
1 5 10 15
Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile
20 25 30
Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser
35 40 45
Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly
50 55 60
Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr
65 70 75 80
Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu
85 90 95
Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro
100 105 110
Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg
115 120 125
Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro
130 135 140
Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser
145 150 155 160
Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr
165 170 175
Ala Ser
<210> 3
<211> 73
<212> PRT
<213> （人工序列）
<400> 3
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 Arg Gly Arg Gly Tyr
20 25 30
Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile
35 40 45
His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys Lys
50 55 60
Asn Asp Trp Lys His Asn Ile Thr Gln
65 70
<210> 4
<211> 81
<212> PRT
<213> （人工序列）
<400> 4
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 Tyr Ala Glu Gly Thr Phe Ile Ser Asp
35 40 45
Tyr Ser Ile Ala Met Asp Lys Ile His Gln Gln Asp Phe Val Asn Trp
50 55 60
Leu Leu Ala Gln Lys Gly Lys Lys Asn Asp Trp Lys His Asn Ile Thr
65 70 75 80
Gln
<210> 5
<211> 282
<212> PRT
<213> （人工序列）
<400> 5
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 Arg Gly Arg Gly Tyr
20 25 30
Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile
35 40 45
His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys Lys
50 55 60
Asn Asp Trp Lys His Asn Ile Thr Gln Asp Ser Asp Glu Thr Gly Phe
65 70 75 80
Glu His Ser Gly Leu Trp Val Ser Val Leu Ala Gly Leu Leu Leu Gly
85 90 95
Ala Cys Gln Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe
100 105 110
Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln
115 120 125
Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala
130 135 140
Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro
145 150 155 160
Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln
165 170 175
Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala
180 185 190
Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln
195 200 205
Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro
210 215 220
His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro
225 230 235 240
Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln
245 250 255
Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly Leu
260 265 270
Glu Ala Val Arg Ser Pro Ser Phe Glu Lys
275 280
<210> 6
<211> 251
<212> PRT
<213> （人工序列）
<400> 6
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 Arg Gly Arg Gly Tyr
20 25 30
Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile
35 40 45
His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys Lys
50 55 60
Asn Asp Trp Lys His Asn Ile Thr Gln Ala Asp Ser Ser Pro Leu Leu
65 70 75 80
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
85 90 95
Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
100 105 110
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
115 120 125
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
130 135 140
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
145 150 155 160
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
165 170 175
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Asn Lys
180 185 190
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro
195 200 205
Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala
210 215 220
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly
225 230 235 240
Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
245 250
<210> 7
<211> 178
<212> PRT
<213> （人工序列）
<400> 7
Ala Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg
1 5 10 15
Tyr Leu Tyr Thr Asp Asp Ala Gln Arg Thr Glu Ala His Leu Glu Ile
20 25 30
Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser
35 40 45
Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly
50 55 60
Val Arg Thr Pro Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr
65 70 75 80
Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu
85 90 95
Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro
100 105 110
Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg
115 120 125
Gly Pro Ala Arg Phe Leu Pro Leu Pro Phe Leu Pro Pro Ala Leu Pro
130 135 140
Glu Pro Pro Gly Ile Leu Gly Pro Gln Pro Pro Asp Val Gly Ser Ser
145 150 155 160
Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr
165 170 175
Ala Ser
Claims (11)
1.一种融合蛋白，其特征在于，所述融合蛋白的氨基酸序列如SEQ ID NO：5或SEQ IDNO：6所示。
2.如权利要求1所述的融合蛋白，其特征在于，所述融合蛋白还包括药学上可接受的半衰期延长方式的修饰，所述的修饰为聚合物修饰、非结构化肽链修饰、弹性蛋白样多肽修饰、血清蛋白修饰、免疫球蛋白修饰和免疫球蛋白的Fc区修饰的一种或多种。
3.编码权利要求1所述融合蛋白的基因。
4.携带权利要求3所述基因的载体。
5.含有权利要求4所述载体的微生物细胞。
6.如权利要求1所述的融合蛋白的制备方法，其特征在于，包括以下步骤：
S1：在权利要求5所述的微生物细胞中表达所述融合蛋白；
S2：分离、纯化所述融合蛋白。
7.一种治疗代谢疾病的药物组合物，其特征在于，含有权利要求1所述的融合蛋白，所述治疗代谢疾病为抑制体重增加、降低血脂和血糖、提高胰岛素敏感性、降低肝脏重量和肝脏甘油三酯的含量、修复肝脏损伤或改善非酒精性脂肪性肝炎。
8.如权利要求7所述的治疗代谢疾病的药物组合物，其特征在于，还包括药学上可接受的载体、赋形剂和稀释剂中的一种或多种。
9.如权利要求8所述的治疗代谢疾病的药物组合物，其特征在于，所述药物组合物的给药途径为口服、腹腔注射、皮下注射、静脉注射或肌肉注射。
10.如权利要求1或2所述的融合蛋白、如权利要求7-9任一项所述的药物组合物在制备治疗代谢疾病的药物中的应用，所述代谢疾病为糖尿病、肥胖或肝炎。
11.如权利要求10所述的应用，其特征在于，所述融合蛋白的剂量为1-100 mg/kg。
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| PCT/CN2022/073492 WO2022257479A1 (zh) | 2021-06-10 | 2022-01-24 | 一种治疗代谢疾病的融合蛋白及其制备方法和应用 |
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| CN113956344A (zh) * | 2021-10-14 | 2022-01-21 | 江南大学 | 一种新型治疗肝癌的fgf类似物及其应用 |
| CN113912699A (zh) * | 2021-10-14 | 2022-01-11 | 江南大学 | 一种新型治疗乳腺癌的fgf类似物及其应用 |
| CN114874332B (zh) * | 2022-03-30 | 2023-01-10 | 呈诺再生医学科技(珠海横琴新区)有限公司 | 经修饰的rnf112作为治疗als药物的应用 |
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