CN116284313A - 一种新型多肽在制备糖尿病药物中的应用 - Google Patents
一种新型多肽在制备糖尿病药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物医学领域，具体地涉及用于制备治疗糖尿病药物的干预多肽，包括：（a）SEQ ID No 1；（b）多肽（a）与穿膜肽元件形成的融合蛋白；（c）由多肽（a）或（b）中经过缺失、插入或置换一个或几个氨基酸且与（a）或（b）中所述的多肽分子具有相同生物学功能的多肽衍生物。本发明在细胞水平和动物实验均进行了大量的筛选和验证，同时利用临床患者的血清样本进行了检测，证实了所述多肽能够特异性的降低血糖水平，促进细胞摄入葡萄糖，促进糖原合成，从而改善糖尿病症状；它仅影响葡萄糖的代谢，因此副作用小，半衰期较长，具有重大的临床意义。
Description
技术领域
本发明涉及生物医学领域，具体地涉及一种新型多肽在制备糖尿病药物中的应用。
背景技术
糖尿病（diabetes mellitus,DM），是一种代谢性疾病，是由胰岛素分泌受损及各种外周胰岛素抵抗所致的慢性血糖增高状态。长期血糖控制不佳会导致心脑血管、眼、肾、神经等组织器官的渐进性损害，进而致残甚至致死。
糖尿病的诊断，目前依赖于血糖检测，包括，空腹血浆葡萄糖（FPG），糖化血红蛋白（HbA1c）和口服葡萄糖耐量试验。与FPG相比，OGTT对于诊断糖尿病和糖耐量受损更为敏感，但操作不便且耗时，HbA1c因为人群中存在较大比例的糖化血红蛋白变异体，可能导致常规检验方法得到的HbA1c结果假性偏高或偏低，大大降低了HbA1c的诊断价值。
糖尿病按照其病因主要分为两大类；I型糖尿病，由于自身免疫介导的胰岛β细胞破坏导致的胰岛素分泌功能缺陷引发；II型糖尿病，胰岛素抵抗引发。糖尿病最常见的临床表现为高血糖，无论I型还是II型糖尿病患者，通常会出现高血糖相关的症状，如尿频、多饮、体位性低血压、脱水、体重减轻、视物模糊等，或者无症状，因此，其诊断可能会延误很多年，甚至有些患者最先出现的临床表现为糖尿病并发症的症状。
对于糖尿病的治疗，主要是通过控制高血糖来改善症状以及预防并发症及减少低血糖发作，通常结合饮食与运动治疗。I型糖尿病，补充胰岛素；II型糖尿病，口服降糖药，胰岛素，或者二者联用。这些治疗，往往需要每天给药，对于患者及家庭监护要求繁琐。
因此，本领域还迫切需要开发可用于治疗或预防糖尿病，副作用较少且半衰期较长的药物。
发明内容
针对上述问题，本发明的目的是提供一种可用于治疗或预防糖尿病且副作用较低的治疗剂及其应用。本发明提供一种在葡萄糖的摄入和糖原合成的不同层面上，对葡萄糖进行调控，从而降低血糖水平的自噬相关因子ATG7。
为了实现上述目的，本发明提供了如下技术方案。
本发明提供了一种新型多肽，其特征在于，所述多肽的氨基酸序列包括SEQ ID No1。
进一步地，所述多肽来源于人的ATG7蛋白。
本发明还提供了一种新型多肽在制备用于治疗糖尿病药物中的应用，其特征在于，所述多肽包括：
（a）权利要求1所述新型多肽；
（b）多肽（a）与穿膜肽元件形成的融合蛋白；
（c）由多肽（a）或（b）中经过缺失、插入或置换一个或几个氨基酸且与（a）或（b）中所述的多肽分子具有相同生物学功能的多肽衍生物。
进一步地，所述多肽通过直接激活Insulin信号通路中的信号传递因子，增加葡萄糖的摄入和糖原合成，减少葡萄糖的生成，调控葡萄糖代谢。
进一步地，所述药物包括：
（a）制备预防和/或治疗糖尿病的药物；
（b）降低血糖水平的药物；
（c）制备葡萄糖摄取和糖原合成的激动剂。
优选地，所述药物的剂型为任何药物治疗学上可接受的剂型。
优选地，所述药物的剂量为任何药物治疗学上可接受的剂量。
本发明还提供了一种多聚核苷酸序列，其特征在于，所述多聚核苷酸序列能编码权利要求3中所述的多肽。
本发明还提供了一种药物组合物，其特征在于，所述药物组合物包括权利要求3所述的多肽和药学上可接受的载体或赋形剂。
与现有技术相比本发明的有益效果。
本发明首次发现细胞自噬相关因子ATG7参与了葡萄糖的代谢调控。ATG7在葡萄糖的摄入和糖原合成的不同层面上，对葡萄糖进行调控，从而降低血糖水平。
此外，本发明还首次证实了来源于人ATG7蛋白第626-673位氨基酸序列或含有上述氨基酸序列的ATG7片段，能够特异性的降低血糖水平，促进细胞摄入葡萄糖，促进糖原合成，从而改善糖尿病症状；它仅影响葡萄糖的代谢，因此副作用小，半衰期较长。
附图说明
图1显示不同人群外周血血清中ATG7的蛋白水平。其中，A为与非糖尿病对照组相比，糖尿病患者外周血的血清中，ATG7的蛋白水平明显增高；B为ROC曲线分析显示AUC=0.8446。
图2显示I型糖尿病模型（STZ）小鼠，外周血的血清中和肝组织中Atg7的表达水平。其中A为与对照组小鼠相比，STZ小鼠的血清中，Atg7蛋白水平明显增高；B为肝组织中Atg7蛋白水平降低。
图3显示ATG7参与葡萄糖的代谢调控。其中，a为ATG7缺失导致原代肝细胞摄取葡萄糖的能力下降；b为ATG7缺失导致原代肝细胞内的糖原缺失；c为ATG7缺失导致原代肝细胞中葡萄糖生成增加；d为ATG7调控肝细胞内的糖原合成；e为胰岛素介导的糖原合成依赖于ATG7的表达；f为胰岛素（Insulin）介导的信号通路依赖于ATG7的表达；g为胰岛素受体IR/IGF-1R与底物IRS1的结合依赖于ATG7。
图4显示Aap2调控Insulin信号通路影响葡萄糖的代谢。其中，a为Aap2调控原代MEF细胞中胰岛素介导的信号通路；b为Aap2调控HepG2肝细胞中胰岛素介导的信号通路；c为Aap2调控Huh7肝细胞中胰岛素介导的信号通路；d为Aap2增加原代肝细胞中葡萄糖的摄入；e为Aap2增加原代肝细胞中糖原合成；f为Aap2降低葡萄糖的生成。
图5显示Aap2调控STZ小鼠的血糖水平。其中，a为Aap2降低STZ小鼠的血糖水平，n=9只/组；b为Aap2增加肝中糖原的合成，n=9只/组；c为Aap2降低糖耐量，n=8只/组；d为AUC结果。
具体实施方式
下面通过实验结合附图对本发明给与进一步的说明，以下所述仅为本发明的优选实施例，它们不应被用来解释或限制本发明的范围。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围内。应理解，下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册（New York：Cold Spring Harbor Laborary Press,1989）中所述的条件，或按照制造厂商所建议的条件。
一、实施例中涉及的通用方法。
1. Elisa检测血清中ATG7的蛋白水平：采集全血后，室温静置15-30min，1000-2000g，4℃离心10min，上层为血清。Elisa检测血清中ATG7的蛋白水平，具体使用步骤参见试剂盒说明书。
2. STZ（Streptozotocin）I型糖尿病小鼠模型的构建：6-8周的C57雄性小鼠，标记，称重，记录基础的血糖值。每日腹腔注射STZ（50mg/kg），连续注射5天。14-16天后，称重，测定血糖值，确定STZ糖尿病小鼠模型的建立。
3. 体内血糖水平检测：剪鼠尾末端，利用罗氏血糖仪和血糖试纸，测定小鼠体内的血糖水平。
4. Atg7敲除鼠的原代胚胎肝（Mouse Embryonic Hepatocyte，MEH）细胞的培养：Atg7杂合鼠交配后，怀孕母鼠（E14）取胚胎小鼠，取肝脏，胶原酶消化，培养48小时后，按实验需求传代接种。
5.原代肝细胞的培养：C57小鼠断颈致死后，取肝脏，剪碎研磨，离心，胰酶消化，离心，接种于鼠尾胶原上。
6. 肝糖原检测：取小鼠的肝组织，或者原代培养的胚胎肝细胞，测定肝糖原，具体实验步骤参见试剂盒说明书。
7. 葡萄糖摄取实验检测：原代培养的胚胎肝细胞，给予Aap24小时后，测定葡萄糖摄取情况，具体实验步骤参见试剂盒说明书。
8. 葡萄糖生成实验检测：原代培养的胚胎肝细胞或肝细胞，在葡萄糖产生培养基（不含酚红的无糖DMEM,20mM乳酸钠和2mM丙酮酸钠）中孵育4小时，取上清，测定葡萄糖浓度，具体实验步骤参见试剂盒说明书，BCA法测定样品蛋白浓度，作为样品校准。
9. 体外葡萄糖水平检测：细胞在RIPA裂解液中，4℃裂解30min，将裂解液在13000rpm，4℃，离心20min，分离后取上清液，检测葡萄糖水平，具体实验步骤参见试剂盒说明书，BCA法测定样品蛋白浓度，作为样品校准。
10. 糖耐量检测实验：禁食16小时的小鼠腹腔注射葡萄糖，每公斤体重注射1g葡萄糖。在0、15、30、50、120min测量血糖水平。使用0 (BG0)、30 (BG30)、60 (BG60)、90(BG90)和120 (BG120)min的血糖水平，通过以下公式计算IPGTT结果的曲线下面积(AUC)：AUC (min·mg/dL) = 30min × [1/2 × (BG0 + BG120) + 1 × (BG30 + BG60 +BG90)]。
11. 蛋白免疫印迹（Western blotting）：细胞在RIPA裂解液中，4℃裂解30min后，13000rpm，4℃，离心20min，取上清液。BCA法测定样品蛋白浓度并调整至相同浓度。加入上样缓冲液，混匀后95℃，10min，蛋白质SDS聚丙烯酰胺凝胶电泳，电转至PVDF膜，用5%的脱脂牛奶室温封闭1小时，抗体稀释液稀释一抗至合适浓度，4℃过夜。PBST洗3次后，二抗室温孵育1-4小时，PBST洗3次，ECL显影。
12. 细胞培养和转染：人肝癌细胞株HepG2用10%FBS，1%NEAA的MEM培养，人肝癌细胞株Huh7和人子宫内膜癌KLE细胞株用10%FBS的DMEM培养液培养，原代胚胎肝细胞和原代肝细胞用15%FBS的DMEM培养液培养。所有转染均用Lipofectamin 3000（Invitrogen）完成。
13. 免疫共沉淀实验：细胞在RIPA裂解液中，4℃裂解30min后，13000rpm，4℃，离心20min，取上清液，BCA法测定样品蛋白浓度。定量取上清液加入相应抗体，4℃孵育过夜，加入protein A/G-beads，4℃孵育4-6小时。免疫沉淀反应后，4℃、3000g离心5min，弃上清，protein A/G-beads洗3次后，加入2×SDS加样缓冲液40μL，95℃、10min，Western blotting检测分析。
二、实施例中实验所用抗体，试剂盒和药品。
1.人ATG7的Elisa检测试剂盒，武汉华美；鼠ATG7的Elisa检测试剂盒，LsBio。
2. BIOVISION的糖原检测，葡萄糖摄取检测试剂盒。
3. Sigma的葡萄糖检测试剂盒。
三、实施例中实验所用商业化抗体分别来自以下公司。
1. Sigma的兔抗ATG7抗体，鼠抗GFP抗体，鼠抗α-tubulin抗体。
2. Santa Cruz的鼠抗ATG7抗体，鼠抗IR抗体。
3. CST的兔抗IRS-1,IRS-1磷酸化，AKT,AKT磷酸化，兔抗GFP抗体。
四、除非特别说明，实施例中其他药品及试剂均来自Sigma公司。
五、实验动物：C57小鼠，来自于北京维通利华实验动物技术有限公司。
六、由上海强耀生物科技有限公司直接合成本申请的Aap2肽。
实施例1 Elisa检测血清中ATG7的蛋白水平。
1.1糖尿病患者和正常人血清中ATG7的蛋白水平检测。
收集中国医科大学附属第一医院的糖尿病患者和正常人的外周血样品，提取血清，Elisa检测，见通用方法1。
结果显示：与正常组相比，糖尿病患者血清中的ATG7蛋白水平，明显增高，见图1A，由此可见，在糖尿病患者的外周血血清中，ATG7的蛋白水平显著高于正常人群。ROC曲线分析显示AUC=0.8446，见图1B。可见ATG7的蛋白水平对于区分糖尿病和非糖尿病对照而言，特异度和灵敏度都非常高。
1.2 STZ糖尿病模型鼠的外周血血清中ATG7蛋白水平检测。
1.2.1 STZ糖尿病模型鼠构建，见通用方法2和3。
1.2.2 收集STZ糖尿病模型鼠和正常C57鼠的外周血样品，提取血清，Elisa检测，见通用方法1。
结果表明，与正常组小鼠相比，STZ模型鼠血清中的Atg7蛋白水平，明显增高，见图2A。
1.3 肝组织中Atg7的蛋白表达水平检测。
取STZ模型鼠和正常鼠的肝组织，加入RIPA裂解液匀浆，4℃涡旋振荡45min，13000rpm，4℃，离心20min，取上清液，BCA法测定样品蛋白浓度，并调整至相同浓度。蛋白免疫印迹检测，见通用方法8。
结果表明，与正常组小鼠相比，STZ小鼠肝组织中的Atg7蛋白水平减低，见图2B。
实施例2 ATG7参与Insulin介导的葡萄糖代谢的调控。
2.1原代胚胎肝细胞中葡萄糖代谢的检测。
2.1.1 原代胚胎肝细胞的培养，见通用方法4。
2.1.2 原代胚胎肝细胞中检测葡萄糖摄入、糖原合成和葡萄糖的生成，见通用方法5、6和7。
结果表明，Atg7的缺失，导致原代胚胎肝细胞中，葡萄糖摄入减少，糖原合成减少，葡萄糖的生成增加，见图3a，3b和3c。
2.2 ATG7调控糖原合成
2.2.1 HepG2细胞分别转染ATG7siRNA或myc-ATG7质粒后，检测细胞内的糖原表达水平，见通用方法5和10。
2.2.2 HepG2细胞转染ATG7siRNA后，给予Insulin刺激4小时，检测细胞内的糖原表达水平，见通用方法5和10。
结果表明，ATG7缺失，糖原合成减少；ATG7表达增加，糖原合成增加；ATG7调控糖原合成，见图3d。
Insulin介导的糖原合成的增加，依赖于ATG7的表达，见图3e。
2.3 ATG7调控的Insulin信号通路的检测。
2.3.1原代培养的MEF细胞中，给予Insulin刺激，检测WT细胞和KO (Atg7-/-)细胞中，信号通路的改变。
结果表明，Insulin刺激时，Atg7不影响Insulin受体IR/IGF-1R的激活；底物IRS1和下游信号AKT的激活，受Atg7调控，见图3f。
2.3.2 免疫共沉淀实验检测，ATG7缺失时，受体IR/IGF-1R与底物IRS1的结合变化，见通用方法11。
结果表明，Insulin增加IR/IGF-1R与IRS1的结合，ATG7缺失时，IR/IGF-1R与IRS1的无法结合，导致Insulin信号通路的阻断，见图3g。
实施例3 本发明多肽Aap2调控Insulin信号通路影响葡萄糖的代谢。
3.1 Aap2调控Insulin信号通路
Insulin或Aap2刺激原代MEF细胞、HepG2细胞和Huh7细胞，WB检测Insulin信号通路。
结果表明，Aap2可以直接激活Insulin信号通路中的信号传递因子，见图4a、4b和4c。
3.2 Aap2调控葡萄糖的代谢
在原代培养的肝细胞中，给予Aap2，24小时后，检测葡萄糖的摄入，糖原合成和葡萄糖的生成，见通用方法6、7和8。
结果表明Aap2增加葡萄糖的摄入和糖原合成，减少葡萄糖的生成，Aap2调控葡萄糖代谢，见图4d、4e和4f。
实施例4 STZ糖尿病模型鼠检测Aap2降低血糖的作用。
STZ小鼠，每隔一天腹腔注射Aap2，检测血糖水平，10天后，断颈处死，取肝组织检测糖原，见通用方法3和6。
结果表明，Aap2降低STZ小鼠的血糖水平，n=9只/组，见图5a；并增加STZ小鼠肝中的糖原合成，n=9只/组，见图5b。
STZ小鼠腹腔注射Aap2，24小时后，糖耐量检测实验，n=8只/组，见通用方法。
结果表明，STZ小鼠给予Aap2后，糖耐量降低，见图5c，5d为AUC结果。
序列表
<110>中国医科大学
<120>一种新型多肽在制备糖尿病药物中的应用
<141> 2021-12-09
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 48
<212> PRT
<213> Homo sapiens
<400> 1
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Phe Asn Ser Ser His Ser Phe Leu Glu Asp Leu Thr Gly Leu Thr Leu
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Leu His Gln Glu Thr Gln Ala Ala Glu Ile Trp Asp Met Ser Asp Asp
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Claims (9)
1.一种新型多肽，其特征在于，所述多肽的氨基酸序列包括SEQ ID No1。
2.如权利要求1所述的多肽，其特征在于，所述多肽来源于人的ATG7蛋白。
3.一种新型多肽在制备用于治疗糖尿病药物中的应用，其特征在于，所述多肽包括：
（a）权利要求1所述新型多肽；
（b）多肽（a）与穿膜肽元件形成的融合蛋白；
（c）由多肽（a）或（b）中经过缺失、插入或置换一个或几个氨基酸且与（a）或（b）中所述的多肽分子具有相同生物学功能的多肽衍生物。
4.根据权利要求3所述的一种多肽在制备用于治疗糖尿病药物中的应用，其特征在于，所述多肽通过直接激活Insulin信号通路中的信号传递因子，增加葡萄糖的摄入和糖原合成，减少葡萄糖的生成，调控葡萄糖代谢。
5.根据权利要求3所述的一种多肽在制备用于治疗糖尿病药物中的应用，其特征在于，所述药物包括：
（a）制备预防和/或治疗糖尿病的药物；
（b）降低血糖水平的药物；
（c）制备葡萄糖摄取和糖原合成的激动剂。
6.根据权利要求5所述的药物，其特征在于，所述药物的剂型为任何药物治疗学上可接受的剂型。
7.根据权利要求5所述的药物，其特征在于，所述药物的剂量为任何药物治疗学上可接受的剂量。
8.一种多聚核苷酸序列，其特征在于，所述多聚核苷酸序列能编码权利要求3中所述的多肽。
9.一种药物组合物，其特征在于，所述药物组合物包括权利要求3所述的多肽和药学上可接受的载体或赋形剂。
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