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TW201918259A - Oxyntomodulin analogue GLP-1R / GCGR dual target agonist polypeptide for treating idiopathic pulmonary interstitial fibrosis - Google Patents

Oxyntomodulin analogue GLP-1R / GCGR dual target agonist polypeptide for treating idiopathic pulmonary interstitial fibrosis Download PDF

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TW201918259A
TW201918259A TW107139333A TW107139333A TW201918259A TW 201918259 A TW201918259 A TW 201918259A TW 107139333 A TW107139333 A TW 107139333A TW 107139333 A TW107139333 A TW 107139333A TW 201918259 A TW201918259 A TW 201918259A
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蔣先興
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Abstract

Disclosed is a use of a polypeptide compound having dual agonistic effects on the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). The polypeptide compound has the characteristics of a high enzymolysis stability, a high biological activity and zero adverse reaction, etc., can obviously inhibit the fibrosis transformation and proliferation of human pulmonary epithelial cells induced by TGF-[beta]1, and can obviously improve the degree of pulmonary fibrosis in mice induced by bleomycin. Such a dual target agonist polypeptide can be used for preventing or treating pulmonary diseases indicated by fibrotic symptoms.

Description

基於胃泌酸調節素類似物GLP-1R/GCGR雙靶點激動劑多肽治療特發性肺間質纖維化Treatment of idiopathic pulmonary interstitial fibrosis based on oxyntomodulin analogue GLP-1R/GCGR dual-target agonist polypeptide

本發明屬於生物化學技術領域，具體地，涉及一類GLP-1R/GCGR雙靶點激動劑多肽。本發明還涉及上述雙靶點激動劑多肽對特發性肺間質纖維化等伴隨纖維化症狀肺疾病的預防和/或治療用途。The present invention is in the field of biochemical technology and, in particular, relates to a class of GLP-1R/GCGR dual target agonist polypeptides. The present invention also relates to the use of the above-described dual-target agonist polypeptide for the prophylactic and/or therapeutic use of pulmonary diseases accompanied by fibrotic symptoms such as idiopathic pulmonary interstitial fibrosis.

特發性肺纖維化（IPF）是一種原因不明的漸進性肺間質性疾病，表現為患者呼吸困難，肺功能不可逆下降甚至喪失，是慢性非腫瘤疾病中預後較差的一種疾病，死亡率很高，糖皮質激素和免疫抑制劑治療結果不甚理想，患者5年生存率低於50%（Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, et al.Am. J. Respir. Crit. Care Med. 2011 . 183:788–824; Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, et al.Thorax .2011 . 66:462-467.）。IPF在40歲到70歲年齡階段的患者中較多見，而且隨著患者年齡增大，IPF死亡率增高。另外，IPF的發生與發展還與患者的性別以及體重等多因素有關，因為在男性人群中IPF的發生率要高於女性，而且其發展快，存活率也低於女性（Willis BC, Borok Z.Am. J. Physiol. Lung Cell Mol. Physiol. 2012 . 293:525-534.）。大多數間質性肺疾病都有共同的病理基礎過程。初期損傷之後發生肺泡炎，隨著炎性-免疫反應的進展，炎症和異常修復導致肺間質細胞增殖，產生大量的膠原和細胞外基質。肺間質纖維化最終導致肺泡氣體交換單元永久性喪失（Wolters PJ, Collard HR & Jones KD.Annu. Rev. Pathol. Mech. Dis .2014 . 9: 157-179.）。Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown cause. It is characterized by difficulty in breathing and irreversible decline or even loss of lung function. It is a poor prognosis in chronic non-neoplastic diseases, and the mortality rate is very high. High, glucocorticoid and immunosuppressive therapy results are less than ideal, with a 5-year survival rate of less than 50% (Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, et al. Am. J. Respir. Crit Care Med. 2011 . 183:788–824; Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, et al. Thorax . 2011 . 66:462-467.). IPF is more common in patients between the ages of 40 and 70, and IPF mortality increases as the patient ages. In addition, the occurrence and development of IPF is also related to the patient's gender and body weight, because the incidence of IPF is higher in women than in women, and its development is faster, and the survival rate is lower than that of women (Willis BC, Borok Z Am. J. Physiol. Lung Cell Mol. Physiol. 2012 . 293:525-534.). Most interstitial lung diseases have a common pathological basis. Alveolitis occurs after the initial injury, and as the inflammatory-immune response progresses, inflammation and abnormal repair lead to the proliferation of pulmonary interstitial cells, producing a large amount of collagen and extracellular matrix. Pulmonary interstitial fibrosis ultimately leads to permanent loss of alveolar gas exchange units (Wolters PJ, Collard HR & Jones KD. Annu. Rev. Pathol. Mech. Dis . 2014 . 9: 157-179.).

在正常肺組織中，膠原蛋白是其主要細胞外基質（Extra Cellular Matrix, ECM）蛋白，與其他類型的ECM成分構成三維網狀結構，作為肺組織結構的主要骨架。這些ECM蛋白成分對保持肺組織結構的完整性，以及對維持肺上皮及內皮細胞分化狀態起著十分重要的作用。肺臟損傷後，在損傷-炎症-修復的過程中，產生各種細胞因數，而任何一項或多項過程的失調，均可造成ECM代謝異常，從而使生理性癒合轉變為病理性纖維化。In normal lung tissue, collagen is its main extracellular matrix (ECM) protein, which forms a three-dimensional network structure with other types of ECM components, and serves as the main skeleton of lung tissue structure. These ECM protein components play an important role in maintaining the integrity of the lung tissue structure and in maintaining the differentiation of the lung epithelium and endothelial cells. After lung injury, various cytokines are produced during the injury-inflammation-repair process, and any one or more of the process disorders can cause abnormalities in ECM metabolism, thereby transforming physiological healing into pathological fibrosis.

目前對特發性肺纖維化主要的治療策略有抗炎、抗纖維化和抗氧化等。但尚無任何藥物證明對IPF有確切療效。糖皮質激素是傳統的治療肺纖維化的主導藥物，它可以抑制炎症反應，減輕肺泡炎，從而延緩肺纖維化的進程。但目前研究發現它僅對20%的IPF患者有效，並不能延長患者的存活時間。長期服用糖皮質激素存在明顯的副作用，往往會合並肺部的細菌或真菌感染；免疫抑制劑如：環磷醯胺、硫唑嘌呤、環孢素A等能夠減輕機體的免疫反應。但是經常使用不僅存在潛在的嚴重副作用，而且對IPF治療基本無效；吡非尼酮（5甲基1苯基2 -(1 H)吡啶酮）是人工合成分子，也是目前唯一被批准可用於IPF臨床治療的抗纖維化藥。雖然吡非尼酮是現有治療IPF的有效藥物，但作為一種口服藥，在臨床具有較多的副作用，如腸胃不適（噁心、嘔吐、消化不良和腹瀉等）、乏力及光敏性皮疹等。近年來抗肺纖維化藥物的探索越來越受到關注，而且研究工作者通過嘗試不同環節的合成及功能來減輕或調節肺纖維化進程。但目前所有治療對於肺功能指標並無明顯改善。雖然有一些細胞因數製劑對肺纖維化有一定的治療效果，但至今沒有一種能用於臨床治療。At present, the main treatment strategies for idiopathic pulmonary fibrosis are anti-inflammatory, anti-fibrosis and anti-oxidation. However, there is no drug that has proven to be effective against IPF. Glucocorticoid is the traditional drug for the treatment of pulmonary fibrosis. It can inhibit inflammation and reduce alveolitis, thus delaying the progression of pulmonary fibrosis. However, the current study found that it is only effective in 20% of patients with IPF, and does not extend the survival time of patients. Long-term use of glucocorticoids has obvious side effects, often combined with bacterial or fungal infections in the lungs; immunosuppressive agents such as cyclophosphamide, azathioprine, and cyclosporine A can alleviate the body's immune response. However, frequent use not only has potentially serious side effects, but also is essentially ineffective for IPF treatment; pirfenidone (5-methyl 1 phenyl 2 -(1 H)pyridone) is a synthetic molecule and is currently the only approved for IPF. Anti-fibrotic drugs for clinical treatment. Although pirfenidone is an effective drug for the treatment of IPF, as an oral drug, it has many side effects in the clinic, such as gastrointestinal discomfort (nausea, vomiting, indigestion and diarrhea), fatigue and photosensitive rash. In recent years, the exploration of anti-pulmonary fibrosis drugs has attracted more and more attention, and researchers have tried to reduce or regulate the process of pulmonary fibrosis by trying different aspects of synthesis and function. However, at present all treatments have no significant improvement in lung function indicators. Although some cytokine preparations have a certain therapeutic effect on pulmonary fibrosis, none of them have been used for clinical treatment.

博萊黴素（BLM）是臨床治療癌症的藥物，長期用藥可誘導肺部損傷及肺纖維化。因此，BLM誘導的肺纖維化模型是經典的IPF動物模型（Chua FJ, Gauldie J, Laurent GJ. Am J Respir Cell Mol Biol,2005 . 33:9-13.）。Bleomycin (BLM) is a clinically used cancer treatment drug that induces lung damage and pulmonary fibrosis over a long period of time. Thus, the BLM-induced pulmonary fibrosis model is a classic IPF animal model (Chua FJ, Gauldie J, Laurent GJ. Am J Respir Cell Mol Biol, 2005. 33:9-13.).

本發明人在早先的中國專利號：ZL 201510237027.7中，獲得了作為胃泌酸調節素類似物的一類GLP-1R/GCGR雙靶點激動劑，其具有長的半衰期，促胰島素活性，無不良反應，可用於糖尿病等疾病的治療。本發明繼續深入實驗，並提供了該類GLP-1R/GCGR雙靶點激動劑多肽的新生物活性及其治療和適應症用途。The inventors obtained a class of GLP-1R/GCGR dual-target agonists as ghrelin analogs in the earlier Chinese patent number: ZL 201510237027.7, which has a long half-life, insulinotropic activity, and no adverse reactions. It can be used for the treatment of diseases such as diabetes. The present invention continues to be intensively conducted and provides novel biological activities and therapeutic and indication uses of such GLP-1R/GCGR dual-target agonist polypeptides.

本發明的目的在於提供該類GLP-1R/GCGR雙靶點激動劑多肽在對特發性肺間質纖維化及相關肺纖維化等疾病的預防和/或治療用途。It is an object of the present invention to provide a prophylactic and/or therapeutic use of such a GLP-1R/GCGR dual-target agonist polypeptide for diseases such as idiopathic pulmonary interstitial fibrosis and associated pulmonary fibrosis.

本發明人經過大量的實驗研究，證明該類GLP-1R/GCGR雙靶點激動劑多肽對TGF-β誘導的成纖維細胞轉化具有顯著的作用。發明人經過大量的實驗研究證明：能夠有效地延緩，治療肺纖維化進程，在該類GLP-1R/GCGR雙靶點激動劑多肽治療給藥中都能顯著減少肺泡腔內細胞和纖維的堆積、降低膠原沉澱以及肺纖維化標誌蛋白α-SMA表達。The present inventors have conducted extensive experimental studies to demonstrate that such GLP-1R/GCGR dual-target agonist polypeptides have a significant effect on TGF-β-induced fibroblast transformation. The inventors have demonstrated through extensive experimental studies that it can effectively delay the treatment of pulmonary fibrosis and significantly reduce the accumulation of cells and fibers in the alveolar space in the treatment of GLP-1R/GCGR dual-target agonist polypeptides. Reduce collagen deposition and expression of pulmonary fibrosis marker protein α-SMA.

本發明的又一個目的在於提供該類GLP-1R/GCGR雙靶點激動劑多肽新的適應症治療用途。A further object of the invention is to provide a novel indication for the therapeutic use of such GLP-1R/GCGR dual target agonist polypeptides.

該類GLP-1R/GCGR雙靶點激動劑多肽有望作為新一代對特發性肺間質纖維化等疾病的預防或治療藥物。This kind of GLP-1R/GCGR dual-target agonist polypeptide is expected to be a new generation of preventive or therapeutic drugs for diseases such as idiopathic pulmonary interstitial fibrosis.

本發明中涉及含有以下氨基酸序列表示的母體肽的GLP-1R/GCGR雙靶點激動劑多肽： His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Leu-Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-COR1 其中，R1 = -NH2 ; Xaa2 = Aib或D-Ser； Xaa10= Lys或Tyr； Xaa13 = Lys或Tyr； Xaa16 = Ser，Aib，Lys或Glu； Xaa17 = Lys或Arg； Xaa18 = Arg或Ala； Xaa20 = His，Gln，或Lys； Xaa21 =Asp或Glu； Xaa23 = Ile， Val； Xaa24 = Glu 或 Gln； Xaa27 = Met，Leu，Nle； Xaa28 = Asn，Asp， Arg，Ser或不存在； Xaa29 = Gly，Thr或不存在； Xaa30 = Gly或不存在； Xaa31 = Gly或不存在； Xaa32 = Pro或不存在； Xaa33 = Ser，Val或不存在； Xaa34 = Ser或不存在； Xaa35 = Gly或不存在； Xaa36 = Ala或不存在； Xaa37 = Pro或不存在； Xaa38 = Pro或不存在； Xaa39 = Pro或不存在； Xaa40 = Ser或不存在； 所述氨基酸序列中，Xaa10，Xaa16，Xaa17或Xaa20中至少一個為Lys，所述至少一個Lys或所述序列的第12位Lys的側鏈與親脂性的取代基相連，連接方式為所述親脂性的取代基以其羧基與一個橋接基團的氨基形成醯胺鍵，橋接基團的氨基酸殘基的羧基與母體肽的Lys的N-末端殘基上形成一個醯胺鍵連接到母體肽上；所述橋接基團為Glu，Asp和/或(PEG)m ，其中m為2-10的整數；所述親脂性取代基為選自CH3 (CH2 )n CO-或HOOC(CH2 )n CO-的醯基，其中n是10-24的整數。優選的橋接基團可以為Glu-(PEG)m 或Asp-(PEG)m 或(PEG)m ，連接方式如下： The present invention relates to a GLP-1R/GCGR dual-target agonist polypeptide comprising the parent peptide represented by the following amino acid sequence: His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13 -Leu-Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38 -Xaa39-Xaa40-COR1 wherein R 1 = -NH 2 ; Xaa2 = Aib or D-Ser; Xaa10 = Lys or Tyr; Xaa13 = Lys or Tyr; Xaa16 = Ser, Aib, Lys or Glu; Xaa17 = Lys or Arg Xaa18 = Arg or Ala; Xaa20 = His, Gln, or Lys; Xaa21 = Asp or Glu; Xaa23 = Ile, Val; Xaa24 = Glu or Gln; Xaa27 = Met, Leu, Nle; Xaa28 = Asn, Asp, Arg, Ser or absent; Xaa29 = Gly, Thr or absent; Xaa30 = Gly or absent; Xaa31 = Gly or absent; Xaa32 = Pro or absent; Xaa33 = Ser, Val or absent; Xaa34 = Ser or nonexistent Xaa35 = Gly or absent; Xaa36 = Ala or absent; Xaa37 = Pro or absent; Xaa38 = Pro or absent; Xaa39 = Pro or absent; Xaa40 = Ser or absent; Wherein at least one of Xaa10, Xaa16, Xaa17 or Xaa20 is Lys, the at least one Lys or the side chain of the 12th Lys of the sequence is linked to a lipophilic substituent in a manner of the lipophilic substituent Forming a guanamine bond with an amino group of a bridging group, the carboxyl group of the amino acid residue of the bridging group forms a guanamine bond with the N-terminal residue of Lys of the parent peptide to the parent peptide; said bridging The group is Glu, Asp and/or (PEG) m , wherein m is an integer from 2 to 10; the lipophilic substituent is selected from CH 3 (CH 2 ) n CO- or HOOC(CH 2 ) n CO- A thiol group, where n is an integer from 10 to 24. A preferred bridging group can be Glu-(PEG) m or Asp-(PEG) m or (PEG) m in the following manner:

本發明中涉及的化合物基於理論分子內橋可以穩定分子的螺旋結構，從而提高了針對GLP-1R或GCGR的效力和/或選擇性。本發明化合物在序列中攜帶一個或多個分子內橋。這樣的橋是由兩個氨基酸殘基的側鏈之間形成，所述兩個氨基酸殘基通常被線性序列中的三個氨基酸所分隔。例如所述橋可在殘基對12與16、16與20、17與21或者20與24側鏈之間形成。兩個側鏈可通過離子相互作用或通過共價鍵彼此相連接。因此，這些殘基對可包含帶相反電荷的側鏈，從而通過離子相互作用形成鹽橋。例如，一個殘基可以是Glu或Asp，而另一殘基可以是Lys或Arg，Lys與Glu配對以及Lys與Asp配對分別還能夠反應形成內醯胺環。The compounds involved in the present invention can stabilize the helical structure of the molecule based on a theoretical intramolecular bridge, thereby increasing the potency and/or selectivity against GLP-1R or GCGR. The compounds of the invention carry one or more intramolecular bridges in the sequence. Such a bridge is formed between the side chains of two amino acid residues that are typically separated by three amino acids in a linear sequence. For example, the bridge can be formed between residue pairs 12 and 16, 16 and 20, 17 and 21 or 20 and 24 side chains. The two side chains can be linked to each other by ionic interaction or by covalent bonds. Thus, these pairs of residues may comprise oppositely charged side chains to form a salt bridge by ionic interaction. For example, one residue may be Glu or Asp, and the other residue may be Lys or Arg, Lys is paired with Glu, and Lys is paired with Asp, respectively, to react to form an indoleamine ring.

本發明還提供含有本發明的GLP-1R/GCGR雙靶點激動劑多肽的藥物組合物，以所述GLP-1R/GCGR雙靶點激動劑多肽作為活性成分添加藥學上可接受的載體和/或輔料製成藥物組合物。The present invention also provides a pharmaceutical composition comprising the GLP-1R/GCGR dual-target agonist polypeptide of the present invention, wherein the GLP-1R/GCGR dual-target agonist polypeptide is added as a active ingredient to a pharmaceutically acceptable carrier and/or Or excipients are formulated into pharmaceutical compositions.

本發明多肽對特發性肺間質纖維化等相關肺纖維化疾病具有改善和治療作用。本發明多肽可用於直接或間接治療由特發性肺間質纖維化等伴隨纖維化症狀肺病所引起的或者以其為特徵的病症。The polypeptide of the present invention has an improvement and therapeutic effect on pulmonary fibrosis diseases such as idiopathic pulmonary interstitial fibrosis. The polypeptide of the present invention can be used for the direct or indirect treatment of a condition caused by or characterized by pulmonary disease associated with fibrotic symptoms such as idiopathic pulmonary interstitial fibrosis.

本領域技術人員可以理解，本發明的藥物組合物適用於各種給藥方式，例如口服給藥、經皮給藥、靜脈給藥、肌肉內給藥、局部給藥、經鼻給藥等。根據所採用的給藥方式，可將本發明的多肽藥物組合物製成各種合適的劑型，其中包含至少一種有效量的本發明的多肽和至少一種藥學上可接受的藥用載體。Those skilled in the art will appreciate that the pharmaceutical compositions of the present invention are suitable for use in a variety of modes of administration, such as oral administration, transdermal administration, intravenous administration, intramuscular administration, topical administration, nasal administration, and the like. The pharmaceutical composition of the polypeptide of the present invention may be formulated into various suitable dosage forms comprising at least one effective amount of a polypeptide of the present invention and at least one pharmaceutically acceptable pharmaceutically acceptable carrier, depending on the mode of administration employed.

適當劑型的實例為片劑、膠囊、糖衣片劑、粒劑、口服溶液和糖漿、用於皮膚表面的油膏和藥貼、氣霧劑、鼻噴劑、以及可用於注射的無菌溶液。Examples of suitable dosage forms are tablets, capsules, sugar-coated tablets, granules, oral solutions and syrups, ointments and patches for the skin surface, aerosols, nasal sprays, and sterile solutions for injection.

含有本發明多肽的藥物組合物可以製成溶液或者凍乾粉以用於胃腸外給藥，在使用前可加入適當溶劑或其他可藥用的載體將粉末重新配製，液體配方一般是緩衝液、等滲溶液和水溶液。The pharmaceutical composition containing the polypeptide of the present invention may be formulated into a solution or a lyophilized powder for parenteral administration, and the powder may be reconstituted by adding a suitable solvent or other pharmaceutically acceptable carrier before use. The liquid formulation is generally a buffer, Isotonic solution and aqueous solution.

本發明多肽在藥物組合物中的用量可以在較大範圍內變動，本領域技術人員可以根據一些客觀的因素如疾病的種類、病情嚴重程度、患者體重、劑型、給藥途徑等因素很容易地加以確定。The amount of the polypeptide of the present invention in the pharmaceutical composition can be varied within a wide range, and those skilled in the art can easily according to some objective factors such as the type of the disease, the severity of the disease, the patient's body weight, the dosage form, the administration route and the like. Add to determine.

本發明的優點在於： 1）具有更好的抗肺纖維化生物學活性； 2）在藥物的藥代實驗中顯示穩定性，穩定性好，易於放大生產，成本低； 3）與小分子化合物相比具有更低毒性，安全窗口更大，用量更小。The invention has the advantages of: 1) having better anti-pulmonary fibrosis biological activity; 2) showing stability in drug pharmacokinetic experiments, good stability, easy scale-up production, low cost; 3) and small molecule compounds Compared to lower toxicity, the safety window is larger and the dosage is smaller.

在具體的實施方案中，涉及下述GLP-1R/GCGR雙靶點激動劑多肽，其具有序列： 化合物 1 （涉及 SEQ ID NO:1 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYS-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 2 （涉及 SEQ ID NO:2 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYS-K(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 3 （涉及 SEQ ID NO:3 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2 -PEG2 -CO(CH2 )16 CH3 )-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYS-K(PEG2 -PEG2 -CO(CH2 )16 CH3 )-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 4 （涉及 SEQ ID NO:4 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS 化合物 5 （涉及 SEQ ID NO:5 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 6 （涉及 SEQ ID NO:6 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 7 （涉及 SEQ ID NO:7 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-Aib-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-RAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 8 （涉及 SEQ ID NO:8 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 9 （涉及 SEQ ID NO:9 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2 -PEG2 -CO(CH2 )14 CH3 )-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYS-K(PEG2 -PEG2 -CO(CH2 )14 CH3 )-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 10 （涉及 SEQ ID NO:10 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-Aib-K(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-RAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 11 （涉及 SEQ ID NO:11 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CO2 H)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 12 （涉及 SEQ ID NO:12 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 13 （涉及 SEQ ID NO:13 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CO2 H)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 14 （涉及 SEQ ID NO:14 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 15 （涉及 SEQ ID NO:15 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 16 （涉及 SEQ ID NO:16 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 17 （涉及 SEQ ID NO:17 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Arg-Ala-NH2 H-(d -S)-QGTFTSDYSKYLDS-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-AAHDFVEWLLRA-NH2 化合物 18 （涉及 SEQ ID NO:18 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-EFIEWLLRA-NH2 化合物 19 （涉及 SEQ ID NO:19 ）： His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-Aib-QGTFTSD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2 化合物 20 （涉及 SEQ ID NO:20 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYS-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 21 （涉及 SEQ ID NO:21 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLDS-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-AAHDFVEWLLNGGPSSGAPPPS-NH2 化合物 22 （涉及 SEQ ID NO:22 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CH3 )-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLDS-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-AAHDFVEWLLNGGPSSGAPPPS-NH2 化合物 23 （涉及 SEQ ID NO:23 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )14 CH3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-EFIEWLLRA-NH2 化合物 24 （涉及 SEQ ID NO:24 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CH3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-EFIEWLLRA-NH2 化合物 25 （涉及 SEQ ID NO:25 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CH3 )-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Arg-Ala-NH2 H-(d -S)-QGTFTSDYSKYLDS-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-AAHDFVEWLLRA-NH2 化合物 26 （涉及 SEQ ID NO:26 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-EFIEWLLNGGPSSGAPPPS-NH2 化合物 27 （涉及 SEQ ID NO:27 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )14 CO2 H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CO2 H)-EFIEWLLNGGPSSGAPPPS-NH2 化合物 28 （涉及 SEQ ID NO:28 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CH3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-EFIEWLLNGGPSSGAPPPS-NH2 化合物 29 （涉及 SEQ ID NO:29 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )14 CH3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLDEKAA-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-EFIEWLLNGGPSSGAPPPS-NH2 化合物 30 （涉及 SEQ ID NO:30 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 31 （涉及 SEQ ID NO:31 ） : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -CO(CH2 )14 CH3 )-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 32 （涉及 SEQ ID NO:32 ） ： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -CO(CH2 )16 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -CO(CH2 )16 CH3 )-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 33 （涉及 SEQ ID NO:33 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-Aib-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-RAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 34 （涉及 SEQ ID NO:34 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 35 （涉及 SEQ ID NO:35 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 36 （涉及 SEQ ID NO:36 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CH3 )-RRAQDFVQWLMNTGGPSSGAPPPS-NH2 化合物 37 （涉及 SEQ ID NO:37 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH2 化合物 38 （涉及 SEQ ID NO:38 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH2 化合物 39 （涉及 SEQ ID NO:39 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )16 CO2 H)-RRAQDFVQWLLNTGGPSSGAPPPS-NH2 化合物 40 （涉及 SEQ ID NO:40 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-RRAQDFVQWLLNTGGPSSGAPPPS-NH2 化合物 41 （涉及 SEQ ID NO:41 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH2 化合物 42 （涉及 SEQ ID NO:42 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -CO(CH2 )14 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSDYSKYLD-K(PEG2 -PEG2 -CO(CH2 )14 CH3 )-RRAQDFVQWLLNTGGPSSGAPPPS-NH2 化合物 43 （涉及 SEQ ID NO:43 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -gGlu-CO(CH2 )14 CH3 )-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS 化合物 44 （涉及 SEQ ID NO:44 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -CO(CH2 )14 CH3 )-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS 化合物 45 （涉及 SEQ ID NO:45 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -CO(CH2 )14 CH3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -CO(CH2 )14 CH3 )-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS 化合物 46 （涉及 SEQ ID NO:46 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -CO(CH2 )16 CO2 H)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS 化合物 47 （涉及 SEQ ID NO:47 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS 化合物 48 （涉及 SEQ ID NO:48 ）： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 H-(d -S)-QGTFTSD-K(PEG2 -PEG2 -gGlu-CO(CH2 )16 CO2 H)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPSIn a specific embodiment, the invention relates to a GLP-1R/GCGR dual target agonist polypeptide having the sequence: Compound 1 (involving SEQ ID NO: 1 ): His-(D-Ser)-Gln-Gly-Thr -Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp -Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYS -K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 2 (involving SEQ ID NO: 2 ): His-(D-Ser)-Gln- Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln -Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S) -QGTFTSDYS-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 3 (involving SEQ ID NO: 3 ): His-(D-Ser)-Gln -Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG 2 -PEG 2 -CO(CH 2 ) 16 CH 3 )-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln -Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-A la-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYS-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CH 3 )-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 4 (directed to SEQ ID NO: 4): His- (D-Ser) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CH 3) -Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly -Ala-Pro-Pro-Pro- Ser-NH 2 H- (d -S) -QGTFTSD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CH 3) -SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS compound 5 (directed to SEQ ID NO: 5): His- (D-Ser) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser- gly-Ala-Pro-Pro- Pro-Ser-NH 2 H- (d -S) -QGTFTSD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H) -SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS -NH 2 compound 6 (involving SEQ ID NO: 6 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys ( PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met- Asn-Thr-Gly-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLD-K (PEG 2 -PEG 2 -γGlu-CO ( CH 2 ) 14 CH 3 )-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 7 (involving SEQ ID NO: 7 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys -Tyr-Leu-Asp-Aib-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met- Asn-Thr-Gly-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLD-Aib-K (PEG 2 -PEG 2 -γGlu- CO(CH 2 ) 16 CO 2 H)-RAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 8 (involving SEQ ID NO: 8 ): His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2- γGlu-CO(CH 2 ) 14 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp- Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CH 3) - SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 9 (involving SEQ ID NO: 9 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys (PEG 2 - PEG 2 -CO(CH 2 ) 14 CH 3 )-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-V al-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYS-K( PEG 2 -PEG 2 -CO(CH 2 ) 14 CH 3 )-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 10 (involving SEQ ID NO: 10 ): His-(D-Ser)-Gln-Gly-Thr-Phe -Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-Arg-Ala-Gln-Asp-Phe- Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD-Aib- K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-RAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 11 (involving SEQ ID NO: 11 ): His-Aib-Gln-Gly-Thr-Phe-Thr-Ser- Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CO 2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln -Trp-Leu-Leu-Asp- Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2 ) 14 CO 2 H)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 12 (involving SEQ ID NO: 12 ): His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Al a-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD- K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CH 3 )-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 13 (involving SEQ ID NO: 13 ): His-Aib-Gln-Gly-Thr-Phe -Thr-Ser-Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CO 2 H)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD-K (PEG 2 -PEG 2- γGlu-CO(CH 2 ) 14 CO 2 H)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 14 (involving SEQ ID NO: 14 ): His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys ( PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu- Leu-Asp-Gly-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CH 3) -SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH 2 compound 15 (relates to SEQ ID NO: 15): His -Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO (CH 2 ) 16 CO 2 H)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg -Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD -K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 16 (involving SEQ ID NO: 16 ): His-Aib-Gln-Gly-Thr-Phe-Thr -Ser-Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val -Gln-Trp-Leu-Leu- Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD-K (PEG 2 -PEG 2 -γGlu -CO(CH 2 ) 14 CH 3 )-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 17 (involving SEQ ID NO: 17 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr- Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu -Leu-Arg-Ala-NH 2 H- (d -S) -QGTFTSDYSKYLDS-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H) -AAHDFVEWLLRA-NH 2 compound 18 (SEQ ID involving NO:18 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys (PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg -Ala-NH 2 H-( d -S)-QGTFTSDYSKYLDEKAA-K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-EFIEWLLRA-NH 2 Compound 19 (involving SEQ ID NO: 19 ) : His-Aib-Gln-Gly -Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H) -Ser-Lys-Tyr-Leu-Asp- Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-Aib-QGTFTSD-K (PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH 2 Compound 20 (involving SEQ ID NO: 20 ): His-(D -Ser) -Gln-Gly-Thr- Phe-Thr-Ser-Asp-Tyr-Ser-Lys (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H) -Lys-Leu-Asp-Aib -Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYS-K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 21 (involving SEQ ID NO: 21 ) : His- (D-Ser) -Gln -Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys (PEG 2 -PEG 2 -gGlu-CO (CH 2 ) 16 CO 2 H)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser -Gly-Ala-Pro-Pro- Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLDS-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H) -AAHDFVEWLLNGGPSSGAPPPS-NH 2 Compound 22 (involving SEQ ID NO: 22 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys (PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CH 3 )-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly -Ala-Pro-Pro-Pro- Ser-NH 2 H- (d -S) -QGTFTSDYSKYLDS-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CH 3) -AAHDFVEWLLNGGPSSGAPPPS-NH 2 compound 23 ( References to SEQ ID NO: 23 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala- Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 14 CH 3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH 2 H-( d -S)-QGTFTSDYSKYLDEKAA- K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-EFIEWLLRA-NH 2 Compound 24 (involving SEQ ID NO: 24 ): His-(D-Ser)-Gln-Gly-Thr-Phe -Thr-Ser-Asp-Tyr- Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys (PEG 2 -PEG 2 -gGlu-CO (CH 2) 16 CH 3) -Glu-Phe -Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH 2 H-( d -S)-QGTFTSDYSKYLDEKAA-K(PEG 2 -PEG 2 - γGlu-CO(CH 2 ) 16 CH 3 )-EFIEWLLRA-NH 2 Compound 25 (involving SEQ ID NO: 25 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp- Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CH 3 )-Ala-Ala-His-Asp-Phe-Val-Glu-Trp- Leu-Leu-Arg-Ala- NH 2 H- (d -S) -QGTFTSDYSKYLDS-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CH 3) -AAHDFVEWLLRA-NH 2 compound 26 (SEQ ID involving NO:26 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys (PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLDEKAA-K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-EFIEWLLNGGPSSGAPPPS-NH 2 Compound 27 (involving SEQ ID NO :27 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys (PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 14 CO 2 H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro -Pro-Ser-NH 2 H- ( d -S) -QGTFTSDYSKYLDEKAA-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CO 2 H) -EFIEWLLNG GPSSGAPPPS-NH 2 Compound 28 (involving SEQ ID NO: 28 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu -Lys-Ala-Ala-Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CH 3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser -Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLDEKAA-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CH 3) -EFIEWLLNGGPSSGAPPPS-NH 2 Compound 29 (involving SEQ ID NO: 29 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys- Ala-Ala-Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 14 CH 3 )-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser- gly-Ala-Pro-Pro- Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLDEKAA-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CH 3) -EFIEWLLNGGPSSGAPPPS-NH 2 compound 30 (Involving SEQ ID NO: 30 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)- Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly- Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-SKYL D-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 31 (involving SEQ ID NO: 31 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -CO (CH 2 ) 14 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K(PEG 2 -PEG 2 -CO(CH 2 ) 14 CH 3 )-SKYLD -Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 32 (involving SEQ ID NO: 32 ) : His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -CO( CH 2 ) 16 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CH 3 )-SKYLD- Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 33 (involving SEQ ID NO: 33 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp -Aib-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD-Aib-K(PEG 2 -PEG 2- γGlu-CO(CH 2 ) 14 CH 3 )-RAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 34 (involving SEQ ID NO: 34 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp -Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln- Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD-K (PEG 2 -PEG 2- γGlu-CO(CH 2 ) 16 CO 2 H)-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 35 (involving SEQ ID NO: 35 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser- Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp -Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 36 (involving SEQ ID NO: 36 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr -Ser-Lys-Tyr-Leu-Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu -Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-Q GTFTSDYSKYLD-K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CH 3 )-RRAQDFVQWLMNTGGPSSGAPPPS-NH 2 Compound 37 (involving SEQ ID NO: 37 ): His-(D-Ser)-Gln-Gly-Thr -Phe-Thr-Ser-Asp- Tyr-Ser-Lys-Tyr-Leu-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CH 3) -Arg-Arg-Ala-Gln-Asp -Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD -K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH 2 Compound 38 (involving SEQ ID NO: 38 ): His-(D-Ser)-Gln- gly-Thr-Phe-Thr- Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys (PEG 2 -PEG 2 -gGlu-CO (CH 2) 16 CO 2 H) -Arg-Arg-Ala -Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d - S)-QGTFTSDYSKYLD-K(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 16 CO 2 H)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH 2 Compound 39 (involving SEQ ID NO: 39 ): His-(D- Ser) -Gln-Gly-Thr- Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys (PEG 2 -PEG 2 -gGlu-CO (CH 2) 16 CO 2 H) - Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 16 CO 2 H) -RRAQDFVQWLLNTGGPSSGAPPPS-NH 2 Compound 40 (involving SEQ ID NO: 40 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys (PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro- Pro-Pro-Ser-NH 2 H- (d -S) -QGTFTSDYSKYLD-K (PEG 2 -PEG 2 -γGlu-CO (CH 2) 14 CH 3) -RRAQDFVQWLLNTGGPSSGAPPPS-NH 2 Compound 41 (involving SEQ ID NO: 41 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys (PEG 2 - PEG 2 -CO(CH 2 ) 16 CO 2 H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH 2 Compound 42 (involving SEQ ID NO: 42 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys (PEG 2 -PEG 2 -CO(CH 2 ) 14 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu- Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSDYSKYLD-K(PEG 2 -PEG 2 -CO(CH 2 14 CH 3 )-RRAQDFVQWLLNTGGPSSGAPPPS-NH 2 Compound 43 (involving SEQ ID NO: 43 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 14 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr -Gly-Gly-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H- (d -S) -QGTFTSD-K (PEG 2 -PEG 2 -gGlu-CO (CH 2) 14 CH 3 )-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS Compound 44 (involving SEQ ID NO: 44 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -CO(CH 2 ) 14 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K(PEG 2 -PEG 2 -CO(CH 2 ) 14 CH 3 ) - SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS Compound 45 (involving SEQ ID NO: 45 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys (PEG 2 -PEG 2 -CO(CH) 2 ) 14 CH 3 )-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-L eu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K(PEG 2 -PEG 2 - CO(CH 2 ) 14 CH 3 )-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS Compound 46 (involving SEQ ID NO: 46 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser- Asp-Lys(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp -Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K(PEG 2 -PEG 2 -CO(CH 2 ) 16 CO 2 H)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS Compound 47 (involving SEQ ID NO: 47 ): His-(D-Ser)-Gln-Gly-Thr-Phe-Thr- Ser-Asp-Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val -Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S)-QGTFTSD-K (PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS Compound 48 (involving SEQ ID NO: 48 ): His-(D-Ser)-Gln-Gly-Thr-Phe- Thr-Ser-Asp-Lys(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-G ln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 H-( d -S )-QGTFTSD-K(PEG 2 -PEG 2 -gGlu-CO(CH 2 ) 16 CO 2 H)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS

本發明中所用縮寫具體含義如下 : Boc為叔丁氧羰基，Fmoc為芴甲氧羰基，t-Bu為叔丁基，ivDDe為1-(4,4-二甲基-2,6-二氧代亞環己基)-3-甲基-丁基的脫除與親脂取代基，resin為樹脂，TFA為三氟乙酸，EDT為1,2-乙二硫醇，Phenol為苯酚，FBS為胎牛血清，BSA為牛血清白蛋白，HPLC為高效液相，GLP-1R為胰高血糖素樣肽1受體，GCGR為胰高血糖素受體，GLP-1為胰高血糖素樣肽，mPEG為單甲氧基聚乙烯二醇，OXM為胃泌酸調節素，His為組氨酸，Ser為絲氨酸，D-Ser為D-型絲氨酸，Gln為穀氨醯胺，Gly為甘氨酸，Glu為谷氨酸，Ala為丙氨酸，Thr為蘇氨酸，Lys為賴氨酸，Arg為精氨酸，Tyr為酪氨酸，Asp為天冬氨酸，Trp為色氨酸，Phe為苯丙氨酸，Ile為異亮氨酸，Leu為亮氨酸，Cys為半胱氨酸，Pro為脯氨酸，Val為纈氨酸，Met為蛋氨酸，Asn為天冬醯胺，HomoLys為高賴氨酸，Orn為鳥氨酸，Dap為二氨基庚二酸，Dab為2,4-二氨基丁酸，Nle為正亮氨酸，Aib為2-氨基異丁酸，Palmitoyl為棕櫚醯基團，Cholesteryl為膽固醇基團，AEEA為[2-[2-(氨基)乙氧基]乙氧基]乙酸，CA為4-咪唑基乙醯。 The abbreviations used in the present invention have the following specific meanings : Boc is a tert-butoxycarbonyl group, Fmoc is a fluorenylmethoxycarbonyl group, t-Bu is a tert-butyl group, and ivDDe is 1-(4,4-dimethyl-2,6-dioxo. Resin and lipophilic substituents of resinocyclohexyl)-3-methyl-butyl, resin is resin, TFA is trifluoroacetic acid, EDT is 1,2-ethanedithiol, Phenol is phenol, FBS is tire Bovine serum, BSA is bovine serum albumin, HPLC is high-performance liquid phase, GLP-1R is glucagon-like peptide 1 receptor, GCGR is glucagon receptor, and GLP-1 is glucagon-like peptide. mPEG is monomethoxypolyethylene glycol, OXM is oxyntomodulin, His is histidine, Ser is serine, D-Ser is D-serine, Gln is glutamine, Gly is glycine, Glu Is glutamic acid, Ala is alanine, Thr is threonine, Lys is lysine, Arg is arginine, Tyr is tyrosine, Asp is aspartic acid, Trp is tryptophan, Phe is Phenylalanine, Ile is isoleucine, Leu is leucine, Cys is cysteine, Pro is valine, Val is valine, Met is methionine, Asn is aspartame, HomoLys is High lysine, Orn is ornithine, Dap is diaminopimelic acid, Dab is 2,4-diaminobutyric acid, Nle is norleucine, Aib is 2-aminoisobutyric acid, Palmitoyl is a palmitoyl group, Cholesteryl is a cholesterol group, and AEEA is [2-[2-(amino) Ethoxy]ethoxy]acetic acid, CA is 4-imidazolylethane.

下面將結合實施例對本發明的實施方案進行詳細描述，但是本領域技術人員將會理解，下列實施例僅用於說明本發明，而不應視為限定本發明的範圍。實施例中未注明具體條件者，按照常規條件或製造商建議的條件進行。除非另有說明，否則所用試劑或儀器均可以通過市購獲得。實施例 1 、多肽化合物的合成 材料 : The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, however, the following examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, the reagents or instruments used are commercially available. : Example 1 Synthesis of the compound of polypeptide material

所有的氨基酸購自NovaBiochem公司。如果沒有特別說明，其他所有試劑均為分析純，購自Sigma公司。採用Protein Technologies PRELUDE 6通道多肽合成儀。Phenomenex Luna C18 製備柱（46mm x 250mm）用來純化多肽。高效液相色譜儀為Waters公司產品。質譜分析採用Agilent質譜儀進行測定。以多肽化合物 6 為例說明本發明多肽化合物的合成方法： 結構序列： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 a) 主肽鏈組裝： All amino acids were purchased from NovaBiochem. All other reagents were of analytical grade and were purchased from Sigma unless otherwise stated. A Protein Technologies PRELUDE 6-channel peptide synthesizer was used. A Phenomenex Luna C18 preparative column (46 mm x 250 mm) was used to purify the peptide. The high performance liquid chromatograph is a product of Waters Corporation. Mass spectrometry was performed using an Agilent mass spectrometer. The synthesis method of the polypeptide compound of the present invention is illustrated by taking the polypeptide compound 6 as an example: structural sequence: His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu- Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly- Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 a) Master peptide chain assembly:

按照Fmoc/t -Bu策略在CS336X多肽合成儀（美國 CS Bio公司）上合成0.25mmol規模的如下多肽： Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(ivDde)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂 （1）第一步：將0.75克Rink amide MBHA-LL樹脂（Novabiochem，上樣0.34mmol/g）在二氯甲烷（DCM）中溶脹一個小時，用N ,N -二甲基甲醯胺（DMF）充分洗滌樹脂3次； （2）第二步：以Rink amide樹脂為載體，以偶聯劑由6-氯苯並三氮唑-1,1,3,3-四甲基脲六氟磷酸酯（HCTU），有機鹼N ,N -二異丙基乙胺（DIEPA）兩者按物質的量比1: 1，以N ,N -二甲基甲醯胺（DMF）為溶劑，進行程式反應，依次進行縮合反應連接 Fmoc-Ser(t-Bu)-OH，Fmoc-Pro-OH (3x)，Fmoc-Ala-OH，Fmoc-Gly-OH，Fmoc-Ser(t-Bu)-OH (2x)，Fmoc-Pro-OH，Fmoc-Gly-OH (2x)，Fmoc-Thr(t-Bu)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Met-OH，Fmoc-Leu-OH，Fmoc-Trp(Boc)-OH，Fmoc-Glu(OtBu)-OH，Fmoc-Val-OH，Fmoc-Phe-OH，Fmoc-Asp(OtBu)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ala-OH，Fmoc-Arg(Pbf)-OH (2x)，Fmoc-Lys(ivDde)-OH，Fmoc-Asp(OtBu)-OH，Fmoc-Leu-OH，Fmoc-Tyr(t-Bu)-OH，Fmoc-Lys(Boc)-OH，Fmoc-Ser(t-Bu)-OH，Fmoc-Tyr(t-Bu)-OH，Fmoc-Asp(OtBu)-OH，Fmoc-Ser(t-Bu)-OH，Fmoc-Thr(t-Bu)-OH，Fmoc-Phe-OH，Thr(t-Bu)-OH，Fmoc-Gly-OH，Fmoc-Gln(Trt)-OH，Fmoc-D-Ser(t-Bu)-OH，Boc-His(Boc)-OH得到： Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(ivDde)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂。此後依次用N ,N -二甲基甲醯胺（DMF），二氯甲烷（DCM），甲醇（Methanol），二氯甲烷（DCM），N ,N -二甲基甲醯胺（DMF）充分洗滌樹脂各3次。According to the Fmoc/ t- Bu strategy, a 0.25 mmol scale of the following polypeptide was synthesized on a CS336X peptide synthesizer (CS Bio, USA): Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly- Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu )-Leu-Asp(OtBu)-Lys(ivDde)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)- Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t- Bu)-rink amide resin (1) First step: 0.75 g of Rink amide MBHA-LL resin (Novabiochem, loading 0.34 mmol/g) was swollen in dichloromethane (DCM) for one hour with N , N - II Methylformamide (DMF) thoroughly washes the resin 3 times; (2) Step 2: Rink amide resin as carrier and coupling agent from 6-chlorobenzotriazole-1,1,3,3- Tetramethylurea hexafluorophosphate (HCTU), organic base N , N -diisopropylethylamine (DIEPA) in a ratio of 1:1 by mass to N , N -dimethylformamide ( DMF) is a solvent, the reaction is carried out, and the condensation reaction is carried out in sequence to link Fmoc-Ser(t-Bu)-OH, Fmoc-Pro-OH (3x), Fmoc-Ala-OH, Fmoc-G. ly-OH, Fmoc-Ser(t-Bu)-OH (2x), Fmoc-Pro-OH, Fmoc-Gly-OH (2x), Fmoc-Thr(t-Bu)-OH, Fmoc-Asn(Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Asp (OtBu )-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH (2x), Fmoc-Lys(ivDde)-OH, Fmoc-Asp(OtBu)-OH, Fmoc -Leu-OH, Fmoc-Tyr(t-Bu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(t-Bu)-OH, Fmoc-Tyr(t-Bu)-OH, Fmoc-Asp (OtBu)-OH, Fmoc-Ser(t-Bu)-OH, Fmoc-Thr(t-Bu)-OH, Fmoc-Phe-OH, Thr(t-Bu)-OH, Fmoc-Gly-OH, Fmoc -Gln(Trt)-OH, Fmoc-D-Ser(t-Bu)-OH, Boc-His(Boc)-OH gives: Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu )-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr (t-Bu)-Leu-Asp(OtBu)-Lys(ivDde)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp (Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro- Ser(t-Bu)-rink amide resin. Thereafter, N , N -dimethylformamide (DMF), dichloromethane (DCM), methanol (Methanol), dichloromethane (DCM), and N , N -dimethylformamide (DMF) were used in this order. The resin was washed 3 times each.

在反應中，1）第一個氨基酸Fmoc-Ser(t-Bu)-OH的用量與樹脂用量的物質的量比為1:1~6:1；2）接下來的每次縮合反應中Fmoc保護氨基酸，6-氯苯並三氮唑-1,1,3,3-四甲基脲六氟磷酸酯（HCTU），有機鹼N ,N - 二異丙基乙胺（DIEPA）的用量均過量2~8倍，反應時間為1~5個小時。b) 1-(4,4- 二甲基 -2,6- 二氧代亞環己基 )-3- 甲基 - 丁基 （ivDde）的脫除與親脂取代基的引入： In the reaction, 1) the ratio of the amount of the first amino acid Fmoc-Ser(t-Bu)-OH to the amount of the resin is 1:1~6:1; 2) the next condensation reaction in Fmoc Protected amino acid, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), organic base N , N -diisopropylethylamine (DIEPA) The excess is 2~8 times, and the reaction time is 1~5 hours. b) 1- (4,4- dimethyl-2,6-dioxo-cyclohexylidene) -3-methyl - butyl (ivDde) removal of the lipophilic substituent is introduced:

用N ,N -二甲基甲醯胺（DMF）/二氯甲烷（DCM）= 1:1 (體積比）的溶液中將樹脂洗滌兩次，加入新鮮製備的3.0%的肼水合物N ,N -二甲基甲醯胺（DMF）溶液，將該反應混合物在室溫下振盪10~30分鐘進行肼處理步驟，然後過濾。將肼處理步驟重複5次得到： Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂。此後依次用N ,N -二甲基甲醯胺（DMF），二氯甲烷（DCM），甲醇（Methanol），二氯甲烷（DCM），N ,N -二甲基甲醯胺（DMF）充分洗滌樹脂各3次。The resin was washed twice with a solution of N , N -dimethylformamide (DMF) / dichloromethane (DCM) = 1:1 (volume ratio), and freshly prepared 3.0% hydrazine N was added . A solution of N -dimethylformamide (DMF) was shaken at room temperature for 10 to 30 minutes for the hydrazine treatment step, followed by filtration. The hydrazine treatment step was repeated 5 times to obtain: Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser( tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys-Arg(Pbf)-Arg( Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro -Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide resin. Thereafter, N , N -dimethylformamide (DMF), dichloromethane (DCM), methanol (Methanol), dichloromethane (DCM), and N , N -dimethylformamide (DMF) were used in this order. The resin was washed 3 times each.

加入FmocNH-PEG2 -OH（Quanta BioDesign），2-(7-偶氮苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU），二異丙基乙基胺（DIEPA）的N ,N -二甲基甲醯胺（DMF）混合偶聯液（均過量5倍），振盪2小時後，過濾。此後依次用N ,N -二甲基甲醯胺（DMF），二氯甲烷（DCM），甲醇（Methanol），二氯甲烷（DCM），N ,N -二甲基甲醯胺（DMF）充分洗滌樹脂各3次得到： Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(Fmoc-PEG2 )-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂。此後依次用N ,N -二甲基甲醯胺（DMF），二氯甲烷（DCM），甲醇（Methanol），二氯甲烷（DCM），N ,N -二甲基甲醯胺（DMF）充分洗滌樹脂各3次。Add FmocNH-PEG 2 -OH (Quanta BioDesign), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), two different A mixed solution of propylethylamine (DIEPA) in N , N -dimethylformamide (DMF) (5 times excess) was shaken for 2 hours and then filtered. Thereafter, N , N -dimethylformamide (DMF), dichloromethane (DCM), methanol (Methanol), dichloromethane (DCM), and N , N -dimethylformamide (DMF) were used in this order. Washing the resin three times each time: Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu) -Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(Fmoc-PEG 2 )-Arg(Pbf )-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly -Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide resin. Thereafter, N , N -dimethylformamide (DMF), dichloromethane (DCM), methanol (Methanol), dichloromethane (DCM), and N , N -dimethylformamide (DMF) were used in this order. The resin was washed 3 times each.

20%的呱啶（Piperidine）/N ,N -二甲基甲醯胺（DMF）溶液脫除Fmoc基團（30分鐘，重複脫除兩次），加入Fmoc-PEG2 -OH，2-(7-偶氮苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU），二異丙基乙基胺（DIEPA）的N ,N -二甲基甲醯胺（DMF）混合偶聯液（均過量5倍），進行偶聯反應得到 Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(Fmoc-PEG2 -PEG2 )-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂。此後依次用N ,N -二甲基甲醯胺（DMF），二氯甲烷（DCM），甲醇（Methanol），二氯甲烷（DCM），N ,N -二甲基甲醯胺（DMF）充分洗滌樹脂各3次。20% of Piperidine / N , N - dimethylformamide (DMF) solution to remove Fmoc group (30 minutes, repeated removal twice), added Fmoc-PEG 2 -OH, 2- ( 7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), diisopropylethylamine (DIEPA) N , N -dimethyl The mercaptoamine (DMF) mixed coupling solution (5 times excess) was subjected to a coupling reaction to obtain Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t- Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu- Asp(OtBu)-Lys(Fmoc-PEG 2 -PEG 2 )-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc )-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser( t-Bu)-rink amide resin. Thereafter, N , N -dimethylformamide (DMF), dichloromethane (DCM), methanol (Methanol), dichloromethane (DCM), and N , N -dimethylformamide (DMF) were used in this order. The resin was washed 3 times each.

20%的呱啶（Piperidine）/N ,N -二甲基甲醯胺（DMF）溶液脫除Fmoc基團（30分鐘，重複脫除兩次），然後按照常規條件依次偶聯Fmoc-gGlu-OtBu，加入十六酸（棕櫚酸）得到： Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(PEG2 -PEG2 -C16)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂。此後依次用N ，N -二甲基甲醯胺（DMF），二氯甲烷（DCM），甲醇（Methanol），二氯甲烷（DCM）充分洗滌樹脂各3次後，真空抽乾。20% of Piperidine / N , N - dimethylformamide (DMF) solution to remove Fmoc group (30 minutes, repeated removal twice), and then coupled Fmoc-gGlu- according to normal conditions OtBu, adding hexadecanoic acid (palmitic acid) to give: Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu) -Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(PEG 2 -PEG 2- C16)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)- Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide resin. Thereafter, the resin was sufficiently washed three times with N , N -dimethylformamide (DMF), dichloromethane (DCM), methanol (Methanol) and dichloromethane (DCM), and then evaporated to dryness.

c )多肽全保護的脫除： Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(PEG2 -PEG2 -C16)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide樹脂加入切割液TFA/Phenol/thioanisole/EDT/H2 O（82.5:5:5:2.5:5，體積比）中，升溫，控制裂解液溫度25℃，反應2.5小時。過濾，濾餅用少量裂解液洗滌3次，合併濾液。濾液在攪拌下緩慢倒入冰乙醚中。靜置2小時以上，待沉澱完全，離心，用冰乙醚洗滌沉澱3次，得到粗品化合物： His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2 -PEG2 -γGlu-CO(CH2 )14 CH3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 d )多肽化合物的精製純化： c ) Removal of the complete protection of the polypeptide: Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser( tBu) -Asp (OtBu) -Tyr ( tBu) -Ser (tBu) -Lys (Boc) -Tyr (tBu) -Leu-Asp (OtBu) -Lys (PEG 2 -PEG 2 -C16 )-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t -Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide resin added to cutting solution TFA/Phenol In /thioanisole/EDT/H 2 O (82.5:5:5:2.5:5, volume ratio), the temperature was raised, and the temperature of the lysate was controlled at 25 ° C for 2.5 hours. After filtration, the filter cake was washed 3 times with a small amount of lysate, and the filtrate was combined. The filtrate was slowly poured into ice diethyl ether with stirring. After standing for more than 2 hours, the precipitate was completely precipitated, centrifuged, and washed with ice diethyl ether for 3 times to obtain a crude compound: His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser- Lys-Tyr-Leu-Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met- Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 d ) Purification and purification of peptide compounds:

將所得粗品化合物溶於乙腈（ACN）/H2 O = 1:2（體積比）的溶液中，通過5.0 mm反相C18填充的46mm x 250mm 柱上進行製備型HPLC純化。用30%乙腈（含0.05%三氟乙酸）/H2 O（含0.05%三氟乙酸）為起始，以梯度（1.33%/min的速度增加乙腈的比例），流速為15 mL/min將該柱洗脫30分鐘，收集含有肽的組分，冷凍抽幹，得到HPLC純度大於95%的純品。用液質聯用分析分離出的產物。The obtained crude compound was dissolved in a solution of acetonitrile (ACN) / H 2 O = 1:2 (volume ratio) and purified by preparative HPLC on a <RTIgt;</RTI> Start with 30% acetonitrile (containing 0.05% trifluoroacetic acid) / H 2 O (containing 0.05% trifluoroacetic acid), gradient (inclination rate of acetonitrile at 1.33% / min), flow rate of 15 mL / min The column was eluted for 30 minutes, and the fraction containing the peptide was collected and lyophilized to give a pure product having an HPLC purity of more than 95%. The separated product was analyzed by liquid chromatography.

基於以上合成步驟，合成本發明的如下多肽化合物（表1）：表 1 、本發明實施例中所合成的多肽化合物結構： 實施例 2 、 GLP-1R/GCGR 雙靶點激動多肽對體外人肺 II 型上皮細胞 A549 的增殖抑制效應： Based on the above synthetic steps, the following polypeptide compounds of the present invention were synthesized (Table 1): Table 1 , the structure of the polypeptide compound synthesized in the examples of the present invention: Example 2 , GLP-1R/GCGR dual-target agonistic polypeptide inhibits proliferation of human lung type II epithelial cells A549 in vitro:

炎症細胞使肺組織產生趨化因數和細胞因數來修復和重構肺結構，TGF-β1是巨噬細胞分泌的一種關鍵的促纖維化因數，是成纖維細胞修復反應的中樞。在動物模型和IPF患者的肺組織中，TGF-β1明顯增加。TGF-β1可以調控成纖維細胞的轉移、增殖和分化，這種分化的特點是將導致α-SMA的表達和細胞外基質(ECM)的沉積。Inflammatory cells produce chemokines and cytokines to repair and reconstruct lung structures. TGF-β1 is a key profibrotic factor secreted by macrophages and is the backbone of fibroblast repair responses. TGF-β1 was significantly increased in animal models and lung tissue of IPF patients. TGF-β1 regulates the transfer, proliferation and differentiation of fibroblasts, which are characterized by the expression of α-SMA and the deposition of extracellular matrix (ECM).

實驗方法：（1）將A549細胞消化處理，混勻計數，按照每孔10000個細胞的濃度稀釋，再按照每孔100 μL加入96孔板中，將板子放入37 ℃、5% CO2 的恒溫培養箱中，培養24小時；（2）吸去原來培養基，換為無血清培養基。分組設：①無處理的正常對照組；② 5.0 ng/mL的TGF-β對照組；③候選多肽藥物（15.0 nM）組；④候選多肽藥物（15.0 nM）+5.0 ng/mL TGF-β組；⑤利拉魯肽（15.0 nM）組；⑥利拉魯肽（15.0 nM）+5.0 ng/mL TGF-β組。每組設10個平行孔，繼續在培養箱中培養24小時；（3）24小時後每孔加入10.0 μL MTT，繼續培養4小時，吸去上清液，加入150.0 μL DMSO，混勻15 min後，與酶標儀490 nm處測定各孔吸光值A值。利拉魯肽（Liraglutide）標準品（購於吉爾生化(上海)有限公司，純度＞98%， 醋酸利拉魯肽Cas No.: 204656-20-2.）Experimental methods: (1) A549 cells were digested, mixed and counted, diluted according to the concentration of 10000 cells per well, and then added to a 96-well plate at 100 μL per well, and the plate was placed at 37 ° C, 5% CO 2 . In a constant temperature incubator, culture for 24 hours; (2) aspirate the original medium and replace it with serum-free medium. Grouped: 1 normal control group without treatment; 2 TGF-β control group of 5.0 ng/mL; 3 candidate peptide drug (15.0 nM) group; 4 candidate polypeptide drugs (15.0 nM) + 5.0 ng/mL TGF-β group ; 5 liraglutide (15.0 nM) group; 6 liraglutide (15.0 nM) + 5.0 ng / mL TGF-β group. Set 10 parallel holes in each group and continue to culture in the incubator for 24 hours. (3) Add 10.0 μL of MTT to each well after 24 hours, continue to culture for 4 hours, aspirate the supernatant, add 150.0 μL DMSO, and mix for 15 min. After that, the absorbance A value of each well was measured at 490 nm with a microplate reader. Liraglutide standard (purchased from Jill Biochemical (Shanghai) Co., Ltd., purity >98%, liraglutide acetate Cas No.: 204656-20-2.)

實驗結果：通過人肺II型上皮細胞A549，我們首先用外源性TGF-β1誘導A549細胞增殖，再引入GLP-1R/GCGR雙靶點激動多肽。與正常對照組相比，TGF-β誘導細胞大量增殖，差異極顯著；雙靶點激動多肽1-48在15.0 nM時均具有較強的抑制TGF-β1誘導的A549增殖作用（圖1），結果也顯示了：總體雙靶點激動多肽比利拉魯肽在15.0 nM時對TGF-β誘導的成纖維細胞轉化具有更顯著的作用。實施例 3 、雙靶點激動多肽對肺纖維化的治療藥效研究 1. 材料和方法1.1 動物Experimental results: Through human lung type II epithelial cells A549, we first induced proliferation of A549 cells with exogenous TGF-β1, and then introduced GLP-1R/GCGR dual-target agonistic polypeptide. Compared with the normal control group, TGF-β induced a large number of cell proliferation, and the difference was extremely significant. The double-target agonist polypeptide 1-48 had a strong inhibition of TGF-β1-induced A549 proliferation at 15.0 nM (Fig. 1). The results also show that the overall dual-target agonist polypeptide, liraglutide, has a more pronounced effect on TGF-β-induced fibroblast transformation at 15.0 nM. Example 3 : Therapeutic efficacy of dual-target agonistic polypeptides on pulmonary fibrosis 1. Materials and methods 1.1 Animals

8周齡SPF級雌性C57 BL/6小鼠，20~25 g，由廣東省實驗動物中心提供，並在中山大學藥學院實驗動物中心SPF級實驗室進行實驗。適應性餵養1周。飼養環境：溫度20~25℃，濕度70%，12小時明暗週期可控的房間，自由獲取食物和水。1.2 藥品與試劑Eight-week-old SPF female C57 BL/6 mice, 20-25 g, were provided by the Guangdong Experimental Animal Center and were tested in the SPF laboratory of the Experimental Animal Center of the School of Medicine, Sun Yat-sen University. Adaptive feeding for 1 week. Breeding environment: temperature 20 ~ 25 ° C, humidity 70%, 12 hours of light and dark cycle controllable room, free access to food and water. 1.2 drugs and reagents

博萊黴素（BLM，TCI公司購買）；戊巴比妥鈉、注射用鹽酸博萊黴素、羥脯氨酸（HYP）標準品（購自美國Sigma公司）。1.3 博萊黴素誘導肺纖維化的動物模型的建立，及GLP-1R/GCGR雙靶點激動多肽對肺纖維化的治療藥效研究Bleomycin (BLM, purchased by TCI); sodium pentobarbital, bleomycin hydrochloride for injection, hydroxyproline (HYP) standard (purchased from Sigma, USA). 1.3 Establishment of an animal model of bleomycin-induced pulmonary fibrosis and the therapeutic effect of GLP-1R/GCGR dual-target agonistic polypeptide on pulmonary fibrosis

將144隻SPF級雌性C57 BL/6小鼠隨機分成18組（n＝8），共18組：空白對照組（control），博來黴素組 (Bleomycin) 和多肽藥物給藥組。在上述抑制TGF-β1誘導的A549增殖作用研究結果基礎上，我們選多肽化合物：4, 6, 7, 12, 15, 21, 24, 27, 30, 37, 38, 39，40, 44, 48和利拉魯肽進行對肺纖維化的干預治療效果研究。給藥組分為：4號藥組，6號藥組，7號藥組，12號藥組，15號藥組，21號藥組，24號藥組，27號藥組，30號藥組，37號藥組，38號藥組，39號藥組，40號藥組，44號藥組，48號藥組和利拉魯肽藥組（18組）。144 SPF female C57 BL/6 mice were randomly divided into 18 groups (n=8), a total of 18 groups: control group, bleomycin group and peptide drug administration group. Based on the above studies on the inhibition of TGF-β1-induced proliferation of A549, we selected peptide compounds: 4, 6, 7, 12, 15, 21, 24, 27, 30, 37, 38, 39, 40, 44, 48 And liraglutide for the study of the effect of intervention on pulmonary fibrosis. The drug administration components are: No. 4 drug group, No. 6 drug group, No. 7 drug group, No. 12 drug group, No. 15 drug group, No. 21 drug group, No. 24 drug group, No. 27 drug group, No. 30 drug group , No. 37 drug group, No. 38 drug group, No. 39 drug group, No. 40 drug group, No. 44 drug group, No. 48 drug group and Liraglutide drug group (18 groups).

將所有組C57 BL/6小鼠用2%戊巴比妥鈉（40 mg/kg）腹腔注射麻醉後，博來黴素組氣管內一次性灌注5 mg/kg博來黴素誘導產生肺纖維化。空白對照組（control）小鼠氣管內灌注等量無菌生理鹽水。4, 6, 7, 12, 15, 21, 24, 27, 30, 37, 38, 39, 40, 44, 48組，和利拉魯肽組隔天1次皮下注射200 μg/kg相應的多肽藥物，空白對照組（control），博來黴素組 (Bleomycin) 皮下注射等量無菌生理鹽水，隔天1次，連續給藥21天，取材。1.4 組織病理學檢查All groups of C57 BL/6 mice were anesthetized with intraperitoneal injection of 2% sodium pentobarbital (40 mg/kg). The bleomycin group was intratracheally infused with 5 mg/kg bleomycin to induce pulmonary fibers. Chemical. A control group of mice was intratracheally infused with an equal volume of sterile saline. 4, 6, 7, 12, 15, 21, 24, 27, 30, 37, 38, 39, 40, 44, 48 groups, and the liraglutide group was given a subcutaneous injection of 200 μg/kg of the corresponding peptide once every other day. Drug, blank control group, bleomycin group (Bleomycin) subcutaneous injection of the same amount of sterile saline, once every other day, continuous administration for 21 days, taken. 1.4 histopathological examination

將小鼠右肺下葉剪下固定在體積分數為10%的中性甲醛中，蘇木素-伊紅染色（HE染色）和馬松膠原染色（Masson染色），膠原染色操作嚴格按照Masson 染色試劑盒產品說明書進行。Image J軟體計算相同面積圖片中藍色區域的面積（area），再對面積值利用graphpad Prismversion6軟體進行柱狀圖分析觀察膠原沉積。The right lower lobe of the mouse was cut and fixed in neutral formaldehyde with a volume fraction of 10%, hematoxylin-eosin staining (HE staining) and horseshoe collagen staining (Masson staining). The collagen staining procedure was strictly in accordance with the Masson staining kit. Product manuals are carried out. Image J software calculates the area of the blue area in the same area image, and then uses the graphpad Prismversion6 software to perform histogram analysis to observe collagen deposition.

如圖2所示：小鼠肺臟HE 染色結果： 空白對照組：肺組織結構清晰，無炎症細胞浸潤； 博來黴素纖維化組：見肺泡間隔內成纖維細胞、上皮下肌成纖維細胞明顯增多，毛細血管充血和淋巴細胞、巨噬細胞浸潤的現象，纖維組織增生、肺泡間隔破壞，纖維組織成斑片狀分佈； 雙靶點激動多肽給藥組跟利拉魯肽給藥組相比：候選多肽化合物均不同程度地減輕了肺泡結構紊亂，炎症細胞浸潤；減少肺泡腔內細胞和纖維的堆積、降低膠原沉澱，夠有效地延緩肺纖維化進程，對特發性肺纖維化具有治療作用。As shown in Figure 2: HE staining results of mouse lung: blank control group: clear lung tissue structure, no inflammatory cell infiltration; bleomycin fibrosis group: see alveolar septal fibroblasts, subepithelial muscle fibroblasts Increased, capillary congestion and lymphocyte, macrophage infiltration, fibrous tissue hyperplasia, alveolar septal destruction, fibrous tissue patchy distribution; dual-target agonistic peptide administration group compared with liraglutide administration group : Candidate peptide compounds alleviate the alveolar structural disorder, inflammatory cell infiltration, reduce the accumulation of cells and fibers in the alveolar cavity, reduce collagen deposition, effectively delay the progression of pulmonary fibrosis, and treat idiopathic pulmonary fibrosis effect.

進一步我們選取15, 37, 38, 40，44和48給藥組的肺組織做了Masson染色（圖3）；馬松染色結果半定量分析：用Image J軟體計算相同面積圖片中藍色區域的面積（area），再對面積值利用graphpad軟體進行柱狀圖分析（圖4），每兩組之間進行t-test；羥脯氨酸檢測肺臟中膠原沉積量（圖5）。其結果顯示： 空白對照組：小鼠肺組織馬松染色見在支氣管壁和血管壁存在少量結構性膠原，在肺組織未見明顯的膠原沉積； 博萊黴素組：小鼠肺組織馬松染色顯示在肺組織存在大量束狀藍染的膠原組織； 15號給藥組小鼠肺組織馬松染色只見少量膠原等肺纖維化的標誌物；37號給藥組小鼠肺組織馬松染色見在支氣管壁和血管壁存在少量結構性膠原，在肺組織未見明顯的膠原沉積； 38號給藥組小鼠肺組織馬松染色見在支氣管壁和血管壁存在少量結構性膠原，肺泡腔內的細胞性滲出物並未分泌膠原，所以在肺組織未見明顯的膠原沉積；40號給藥組小鼠肺組織馬松染色除了在支氣管壁和血管壁觀察到少量結構性膠原外，在肺泡壁僅少量膠原沉積現象；44號給藥組小鼠肺組織馬松染色顯示雖然該肺組織肺泡腔內無明顯沉積，但在肺泡壁存在少量膠原沉積現象48號給藥組小鼠肺組織馬松染色顯示在肺泡壁僅僅存在少量沉積和膠原沉積現象。多肽化合物15, 37, 38, 40，44和48均不同程度地減輕了肺泡結構紊亂，炎症細胞浸潤；顯著抑制羥脯氨酸含量，減少肺泡腔內細胞和纖維的堆積、降低膠原沉澱，夠有效地延緩肺纖維化進程，對特發性肺纖維化具有治療作用。Further, we selected Masson staining in the lung tissues of the 15, 37, 38, 40, 44 and 48 administration groups (Fig. 3); semi-quantitative analysis of the results of the horseshoe staining: Calculating the blue areas in the same area image using Image J software Area, and then the area value was analyzed by histogram using graphpad software (Fig. 4), t-test was performed between each group; hydroxyproline was used to detect collagen deposition in the lung (Fig. 5). The results showed: blank control group: horse lung tissue was found to have a small amount of structural collagen in the bronchial wall and blood vessel wall, and no obvious collagen deposition in the lung tissue; bleomycin group: mouse lung tissue horse pine Staining showed a large amount of bundled blue-stained collagen tissue in the lung tissue; the lung tissue of the 15th administration group showed only a small amount of collagen and other markers of pulmonary fibrosis; There was a small amount of structural collagen in the bronchial wall and blood vessel wall, and no obvious collagen deposition in the lung tissue. In the 38th administration group, the lung tissue of the mice was stained with a small amount of structural collagen in the bronchial wall and the blood vessel wall, and the alveolar cavity was found. The cell exudate did not secrete collagen, so no obvious collagen deposition was observed in the lung tissue; the horseshoe staining of the lung tissue of the 40-administered group was observed in the alveolar except for a small amount of structural collagen observed in the bronchial wall and vessel wall. There was only a small amount of collagen deposition on the wall; the horseshoe staining of the lung tissue of the mice in the 44th administration group showed that although there was no obvious deposition in the alveolar space of the lung tissue, there was a small amount of collagen deposition in the alveolar wall. 48 lung of mice administered group Masson staining revealed the presence of only a small amount of collagen deposition and deposition phenomena in the alveolar wall. Polypeptide compounds 15, 37, 38, 40, 44 and 48 all attenuated alveolar structural disorders, inflammatory cell infiltration; significantly inhibited hydroxyproline content, reduced cell and fiber accumulation in the alveolar cavity, reduced collagen deposition, enough Effectively delay the progression of pulmonary fibrosis and have a therapeutic effect on idiopathic pulmonary fibrosis.

α-SMA間接免疫螢光檢查，圖6顯示：雙靶點候選藥物15, 37, 38, 40，44和48在治療肺纖維化過程中都能顯著降低肺纖維化標誌蛋白α-SMA表達。Indirect immunofluorescence assay of α-SMA, Figure 6 shows that dual-target candidate drugs 15, 37, 38, 40, 44 and 48 significantly reduced the expression of pulmonary fibrosis marker protein α-SMA during the treatment of pulmonary fibrosis.

總結：結果表明，本發明涉及到的GLP-1R/GCGR雙靶點激動多肽能夠有效地延緩肺纖維化進程，在治療給藥中都能顯著減少肺泡腔內細胞和纖維的堆積、降低膠原沉澱以及肺纖維化標誌蛋白α-SMA表達。Summary: The results indicate that the GLP-1R/GCGR dual-target agonist polypeptide of the present invention can effectively delay the progression of pulmonary fibrosis, and can significantly reduce the accumulation of cells and fibers in the alveolar cavity and reduce collagen precipitation during therapeutic administration. And pulmonary fibrosis marker protein α-SMA expression.

以上以實例方式對本發明進行了說明，儘管未示出，但本發明保護範圍內的所有多肽均可實現本發明的技術效果，並且本領域技術人員可以本發明進行修改和變形，只要不脫離本發明的精神，均落入本發明所附申請專利範圍內。The present invention has been described by way of example, and although not shown, all the polypeptides within the scope of the present invention can achieve the technical effects of the present invention, and those skilled in the art can make modifications and variations of the present invention without departing from the present invention. The spirit of the invention is within the scope of the appended claims.

無no

圖1為顯示雙靶點激動多肽對TGF-β1誘導的A549增殖的抑制作用的圖（#：表示與對照組相比在95%置信度內（p＜0.05）顯著降低；##：表示與對照組相比在99%置信度內（p＜0.01顯著降低；**：表示與普通膳食組相比在99%置信度內（p＜0.01）顯著升高）。Figure 1 is a graph showing the inhibitory effect of a dual-target agonistic polypeptide on TGF-β1-induced proliferation of A549 (#: indicates a significant decrease in 95% confidence (p < 0.05) compared with the control group; ##: indicates The control group was within 99% confidence (p < 0.01 was significantly reduced; **: indicated a significant increase in 99% confidence (p < 0.01) compared to the normal diet group).

圖2 為顯示雙靶點激動多肽4, 6, 7, 12, 15, 21, 24, 27, 30, 37, 38, 39, 40, 44, 48和利拉魯肽對小鼠肺纖維化治療效果HE染色切片的圖。Figure 2 shows the dual-target agonistic polypeptides 4, 6, 7, 12, 15, 21, 24, 27, 30, 37, 38, 39, 40, 44, 48 and liraglutide for pulmonary fibrosis in mice Effect of HE staining slices.

圖3為顯示雙靶點激動多肽15, 37, 38, 40，44和48對小鼠肺纖維化治療效果Masson染色切片的圖。Figure 3 is a graph showing Masson stained sections of dual-target agonistic polypeptides 15, 37, 38, 40, 44 and 48 for treatment of pulmonary fibrosis in mice.

圖4為顯示馬松染色結果半定量分析的圖（*：表示與對照相比在95%置信度內（p＜0.05）；**：表示與對照相比在99%置信度內（p＜0.01））。Figure 4 is a graph showing semi-quantitative analysis of the results of Marsson staining (*: indicates 95% confidence in comparison with the control (p < 0.05); **: indicates 99% confidence in comparison with the control (p < 0.01)).

圖5為顯示羥脯氨酸檢測肺臟中膠原沉積量的圖（*：表示與對照相比在95%置信度內（p＜0.05）；**：表示與對照相比在99%置信度內（p＜0.01））。Figure 5 is a graph showing the amount of collagen deposition in the lungs detected by hydroxyproline (*: expressed within 95% confidence level compared to the control (p < 0.05); **: expressed within 99% confidence level compared to the control (p<0.01)).

圖6為顯示α-SMA間接免疫螢光檢查-綠色為α-SMA。Figure 6 is a graph showing indirect immunofluorescence of α-SMA - green is α-SMA.

Claims (10)

一種胃泌酸調節素類似物GLP-1R/GCGR雙激動劑多肽在製備用於預防或治療特發性肺間質纖維化等伴隨纖維化症狀肺病的藥物中的應用。Use of an oxyntomodulin analog GLP-1R/GCGR double agonist polypeptide for the preparation of a medicament for preventing or treating pulmonary disease associated with fibrotic symptoms such as idiopathic pulmonary interstitial fibrosis. 根據請求項1所述的應用，其中所述多肽具有以下氨基酸序列表示的母體肽： His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Leu-Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-CO R1 其中，R1 = -NH2 ； Xaa2 = Aib或D-Ser； Xaa10=Lys或Tyr； Xaa13=Lys或Tyr； Xaa16=Ser，Aib，Glu或Lys； Xaa17=Lys或Arg； Xaa18=Arg或Ala； Xaa20=His，Gln或Lys； Xaa21=Asp或Glu； Xaa23=Ile，Val； Xaa24=Glu或Gln； Xaa27=Met，Leu，或Nle； Xaa28=Asn，Asp，Arg，Ser或不存在； Xaa29=Gly，Thr或不存在； Xaa30=Gly或不存在； Xaa31=Gly或不存在； Xaa32=Pro或不存在； Xaa33=Ser，Val或不存在； Xaa34=Ser或不存在； Xaa35=Gly或不存在； Xaa36=Ala或不存在； Xaa37=Pro或不存在； Xaa38=Pro或不存在； Xaa39=Pro或不存在； Xaa40=Ser或不存在。The use according to claim 1, wherein the polypeptide has the parent peptide represented by the following amino acid sequence: His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Leu- Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39- Xaa40-CO R 1 wherein R 1 = -NH 2 ; Xaa2 = Aib or D-Ser; Xaa10 = Lys or Tyr; Xaa13 = Lys or Tyr; Xaa16 = Ser, Aib, Glu or Lys; Xaa17 = Lys or Arg; Xaa18=Arg or Ala; Xaa20=His, Gln or Lys; Xaa21=Asp or Glu; Xaa23=Ile,Val; Xaa24=Glu or Gln; Xaa27=Met, Leu, or Nle; Xaa28=Asn, Asp, Arg, Ser Or absent; Xaa29=Gly, Thr or absent; Xaa30=Gly or absent; Xaa31=Gly or absent; Xaa32=Pro or absent; Xaa33=Ser, Val or absent; Xaa34=Ser or absent; Xaa35=Gly or absent; Xaa36=Ala or absent; Xaa37=Pro or absent; Xaa38=Pro or absent; Xaa39=Pro or absent; Xaa40=Ser or absent. 根據請求項2所述的應用，其中所述Xaa10，Xaa16，Xaa17或Xaa20中至少一個為Lys，所述至少一個Lys或所述序列的第12位Lys的側鏈與親脂性的取代基相連，連接方式為所述親脂性的取代基以其羧基與一個橋接基團的氨基形成醯胺鍵，橋接基團的氨基酸殘基的羧基與母體肽的Lys的N-末端殘基上形成一個醯胺鍵連接到母體肽上，所述橋接基團為Glu，Asp和/或(PEG)m ，其中m為2-10的整數；所述親脂性取代基為選自CH3 (CH2 )n CO-或HOOC(CH2 )n CO-的醯基，其中n是10-24的整數。The use according to claim 2, wherein at least one of the Xaa10, Xaa16, Xaa17 or Xaa20 is Lys, and the side chain of the at least one Lys or the 12th Lys of the sequence is linked to a lipophilic substituent, The linkage is such that the lipophilic substituent forms a guanamine bond with a carboxy group of the amino group of a bridging group, and the carboxy group of the amino acid residue of the bridging group forms a guanamine with the N-terminal residue of the Lys of the parent peptide. a bond to the parent peptide, which is Glu, Asp and/or (PEG) m , wherein m is an integer from 2 to 10; the lipophilic substituent is selected from CH 3 (CH 2 ) n CO - or a thiol group of HOOC(CH 2 ) n CO-, wherein n is an integer from 10 to 24. 根據請求項2所述的應用，其中所述橋接基團為Glu-(PEG)m 或Asp-(PEG)m 或(PEG)m 。The use according to claim 2, wherein the bridging group is Glu-(PEG) m or Asp-(PEG) m or (PEG) m . 根據請求項2所述的應用，其中所述橋接基團在所述氨基酸序列的殘基對12與16、16 與20、17與21或者20與24側鏈之間形成分子橋。The use according to claim 2, wherein the bridging group forms a molecular bridge between the residue pairs 12 and 16, 16 and 20, 17 and 21 or 20 and 24 side chains of the amino acid sequence. 根據請求項2所述的應用，其中與所述親脂性取代基連接的 Lys被HomoLys、Orn、Dap或Dab代替。The use according to claim 2, wherein the Lys linked to the lipophilic substituent is replaced by HomoLys, Orn, Dap or Dab. 根據請求項2至5中任一項所述的應用，其中當所述氨基酸序列的第10、12、16、17或20位為 Lys 時，與所述Lys側鏈連接的親脂性取代基為下述結構之一： 。The use according to any one of claims 2 to 5, wherein when the 10th, 12th, 16th, 17th or 20th position of the amino acid sequence is Lys, the lipophilic substituent attached to the Lys side chain is One of the following structures: . 根據請求項2所述的應用，其中所述母體肽的氨基酸序列選自SEQ ID NO:1，SEQ ID NO:2，SEQ ID NO:3，SEQ ID NO:4，SEQ ID NO:5，SEQ ID NO:6，SEQ ID NO:7，SEQ ID NO:8，SEQ ID NO:9，SEQ ID NO:10，SEQ ID NO:11，SEQ ID NO:12，SEQ ID NO:13，SEQ ID NO:14，SEQ ID NO:15，SEQ ID NO:16，SEQ ID NO:17和SEQ ID NO:18，SEQ ID NO:19，SEQ ID NO:20，SEQ ID NO:21，SEQ ID NO:22，SEQ ID NO:23，SEQ ID NO:24，SEQ ID NO:25，SEQ ID NO:26，SEQ ID NO:27，SEQ ID NO:28，SEQ ID NO:29，SEQ ID NO:30，SEQ ID NO:31，SEQ ID NO:32，SEQ ID NO:33，SEQ ID NO:34，SEQ ID NO:35，SEQ ID NO:36，SEQ ID NO:37，SEQ ID NO:38，SEQ ID NO:39，SEQ ID NO:41，SEQ ID NO:42，SEQ ID NO:43，SEQ ID NO:44，SEQ ID NO:45，SEQ ID NO:46，SEQ ID NO:47和SEQ ID NO:48母體肽的氨基酸序列。The use according to claim 2, wherein the amino acid sequence of the parent peptide is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO :14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22. SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO 39, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47 and SEQ ID NO: 48 The amino acid sequence of the parent peptide. 根據請求項1所述的應用，胃泌酸調節素類似物GLP-1R/GCGR雙激動劑多肽在製備用於預防或直接或間接治療由特發性肺間質纖維化等伴隨肺纖維化症狀所引起的或者以其為特徵的病症。According to the application of claim 1, the oxyntomodulin analog GLP-1R/GCGR double agonist polypeptide is prepared for prevention or direct or indirect treatment of pulmonary fibrosis accompanied by idiopathic pulmonary interstitial fibrosis A condition caused or characterized by it. 根據請求項1所述的應用，其中包含至少一種請求項2至8中任一項所述的有效量的多肽和至少一種藥學上可接受的藥用載體以製備胃泌酸調節素類似物GLP-1R/GCGR雙激動劑多肽藥物組合物，並製成各種合適的劑型。The use according to claim 1, comprising at least one effective amount of the polypeptide of any one of claims 2 to 8 and at least one pharmaceutically acceptable pharmaceutically acceptable carrier to prepare an oxyntomodulin analog GLP -1R/GCGR dual agonist polypeptide pharmaceutical composition and formulated into a variety of suitable dosage forms.
TW107139333A 2017-11-06 2018-11-06 Oxyntomodulin analogue GLP-1R / GCGR dual target agonist polypeptide for treating idiopathic pulmonary interstitial fibrosis TW201918259A (en)

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