CN114106100B - 用于修复皮肤创伤或黏膜损伤的多肽及其应用 - Google Patents
用于修复皮肤创伤或黏膜损伤的多肽及其应用 Download PDFInfo
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Abstract
本发明涉及用于修复皮肤创伤或黏膜损伤的新型多肽及其应用，本发明的一系列多肽与已知多肽无同源性，具有调控细胞增殖和分化的效果；以及涉及所述新型多肽具有修复黏膜损伤或皮肤创伤的用途，以及用于预防、减轻或治疗胃炎、胃溃疡等胃肠疾病的用途。
Description
技术领域
本发明涉及用于修复皮肤创伤或黏膜损伤的新型多肽及其应用，本发明的多肽与已知多肽无同源性，具有修复黏膜损伤或皮肤损伤的效果。
背景技术
皮肤创伤和/或黏膜损伤是很多疾病的共同病理特征。皮肤创伤或皮肤损伤是指正常皮肤(组织)在外界致伤因子如外科手术、外力、热、电流、化学物质、低温以及机体内在因素如局部血液供应障碍等作用下所导致的损害。皮肤损伤常伴有皮肤完整性的破坏以及一定量正常组织的丢失，同时，皮肤的正常功能受损。也称为伤口或者创伤。目前有包括碱性成纤维生长因子、表皮生长因子、血小板生长因子、粒-巨噬细胞集落刺激因子及生长激素等蛋白质/多肽药物具有明显的修复创面、护肤、抗皱和防衰老作用，但这些蛋白质/多肽药物的氨基酸序列较长导致制备成本高、稳定性较差等缺点，因而其应用受到了一定的限制。
表皮生长因子(EGF)是一种由53个氨基酸残基组成的多肽，广泛存在于多种组织器官和体液中，其可促进上皮细胞增殖从而对皮肤起到保护作用。表皮生长因子主要是促进皮肤组织细胞的增殖与生长，使新生的细胞替代衰老的细胞，从而起到抗衰老和护肤保健等功能。表皮生长因子已经被报道具有修复创面作用，因皮肤创面需要消毒、清创时，会应用含碘或双氧水的消毒剂，EGF在此条件下不稳定。生长因子与胃肠愈合有关(J.Surgical Res.2014；17:202-210)，但是EGF经胃肠口服给药时，进入体内后会发生降解，实验中不能达到治疗效果。
人体黏膜是指呼吸系统、消化系统、生殖泌尿系统等腔道或囊状肌性器官的内层，是仅次于皮肤的人体第二大屏障，包括口腔、咽、气管、食道、胃、肠道、阴道、膀胱等，这些器官的管壁或囊壁均有共同的分层规律，又具有与其功能相适应的特点，其胚胎起源、组织结构、病理过程、临床表现、愈后等均有共同特点。
慢性胃炎是一种胃黏膜慢性炎症，是消化内科的常见病和多发病，临床上将不同原因引起的胃黏膜慢性炎症(即在病理上表现为单核细胞和淋巴细胞浸润)和(或)腺体萎缩性病变称为慢性胃炎。黏膜组织的损伤临床上会导致慢性胃炎和消化道溃疡等胃肠道疾病。黏膜上皮的修复有修复(restitution)和再生(regeneration或renewal)两种不同的机制(Cur.Med.Chem.,2008,15,3133-3144)：修复或恢复一般在损伤后几分钟内就开始，通过细胞迁移快速修复浅表病变；再生是通过干细胞和祖细胞的分化和增殖持续再生，持续数天至数月。临床上急慢性胃炎、消化道溃疡治疗药物主要有胃酸抑制剂、胃黏膜保护剂、抗生素等小分子化合物，治疗的效果有限，保护且促进损伤黏膜的修复是的急慢性胃炎、消化道溃疡治疗重点，胃黏膜保护剂主要通过保护损伤黏膜发挥作用，具有组织修复作用。胃黏膜保护药在临床应用过程中存在治疗效果有限，存在有效性差，疗程长、复发率高等问题，尚不能满足各种原因引起的急慢性胃炎及消化道溃疡的临床治疗需求，因此研发对消化道黏膜具有更好保护及组织修复的药物非常有必要，多肽药物具有生物活性强、安全性高的特点，筛选、发现并开发能够治疗皮肤损伤，且可以通过口服治疗黏膜损伤的多肽药物意义重大。
发明内容
为了克服现有技术的不足和缺陷，本发明的目的在于提供一类新型多肽。
第一方面，本发明提供式(I)的化合物或其生理学上相容的盐，其中所述式(I)的化合物如下：
H-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Val-Thr-Val-Ser-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-OH
其中
Xaa1为Pro或缺失；
Xaa2为Val或缺失；
Xaa3为Lys、Pro或缺失；
Xaa4为Leu、Val、Ala或缺失；
Xaa5为Lys、Arg或缺失；
Xaa6为Ser、Thr、Ala或缺失；
Xaa7为Lys、Arg或缺失；
Xaa8为Leu、Val、Ala、Ile或缺失；
Xaa9为Gly、Pro、Ala或缺失；
Xaa10为Asp、Glu、Asn、Val或缺失；
Xaa11为Leu、Val、Ala、Ile、Pro或缺失；
Xaa12为Leu、Val、Ala或缺失；
Xaa13为Pro、Ala、Gly、Val或缺失；
Xaa14为Gly、Ala或缺失；
Xaa15为Gly、Ala或缺失；
Xaa16为Glu、Gln、Asp或缺失；
Xaa17为Glu、Asp、Gln或缺失。
在一实施方案中，Xaa1缺失。
在一实施方案中，Xaa2缺失。
在一实施方案中，Xaa1和Xaa2均缺失。
在一实施方案中，Xaa4-Xaa5-Xaa6-Xaa7为Leu-Lys-Ser-Lys。在一实施方案中，Xaa4-Xaa5-Xaa6-Xaa7-Xaa8为Leu-Lys-Ser-Lys-Leu。在一实施方案中，Xaa4-Xaa5-Xaa6-Xaa7-Xaa8为Lys-Ser-Lys-Leu，其中Xaa4缺失。
在一实施方案中，Xaa9-Xaa10为Gly-Asp。在一实施方案中，Xaa9-Xaa10-Xaa11为Gly-Asp-Leu。在一实施方案中，Xaa9-Xaa10-Xaa11为Gly-Asp-Val、Gly-Asp-Ala或Gly-Asp-Ile。
在一实施方案中，Xaa12为Leu、Val或Ala，优选为Leu。
在一实施方案中，Xaa13-Xaa14为Pro-Gly。在一实施方案中，Xaa13-Xaa14-Xaa15为Pro-Gly-Gly。在一实施方案中，Xaa13-Xaa14-Xaa15-Xaa16-Xaa17为Pro-Gly-Gly-Glu-Glu。在一实施方案中，Xaa13-Xaa14-Xaa15-Xaa16-Xaa17为Ala-Gly-Gly-Glu-Glu、Gly-Gly-Gly-Glu-Glu、Pro-Gly-Gly-Glu-Asp、Pro-Gly-Gly-Gln-Glu、Pro-Gly-Gly-Glu-Gln、Pro-Gly-Gly-Asp-Asp、Pro-Ala-Ala-Asp-Asp、Val-Gly-Gly-Glu-Glu或Pro-Ala-Ala-Gln-Gln。
为方便起见，在本申请中描述本发明的化合物时，省略左侧的H和右侧的OH。
第二方面，本发明提供一种修复皮肤创伤的方法，所述方法包括使皮肤创伤与本发明的化合物或其生理学上相容的盐接触。在优选的实施方案中，所述皮肤创伤与表皮炎症、机械及手术创面、烧伤及烫伤、溃疡、瘘管、褥疮、放化疗引起的皮肤损伤相关，但不限于此。在一实施方案中，所述皮肤创伤是指正常皮肤在外界致伤因子如外科手术、外力、热、电流、化学物质、低温以及机体内在因素如局部血液供应障碍等作用下所导致的损害。在一实施方案中，所述皮肤创伤常伴有皮肤完整性的破坏以及一定量正常组织的丢失。在另一实施方案中，所述皮肤创伤包括皮肤的正常功能受损。
本发明提供一种促进HaCAT细胞增殖的方法，所述方法包括使所述细胞与本发明的化合物或其生理学上相容的盐接触。
第三方面，本发明提供一种修复黏膜损伤的方法，所述方法包括对受试者给予本发明的化合物或其生理学上相容的盐或使黏膜损伤与本发明的化合物或其生理学上相容的盐接触。
在一实施方案中，所述黏膜损伤是消化系统、呼吸系统等腔道内黏膜损伤。
消化系统黏膜损伤与口腔、食道、胃肠疾病相关，所述口腔疾病包括口腔溃疡、口腔炎、牙龈炎、牙周炎等；所述食道疾病包括食管炎、食管溃疡等；所述胃肠疾病包括慢性胃炎、慢性萎缩性胃炎、急性胃炎、胃十二指肠溃疡、功能性胃肠道疾病、消化不良、癌前病变、消化系统肿瘤、胃肠道出血、胃食管返流疾病、急慢性肠炎、溃疡性结肠炎、克罗恩病和放化疗引起的黏膜损伤，但不限于此。
在优选的实施方案中，所述消化道黏膜包括胃黏膜和肠黏膜。在优选的实施方案中，所述黏膜损伤是由刺激性物质或药物、应激状态引起的胃黏膜损伤。所述刺激性物质如盐酸、乙醇或酒精等，所述药物例如非类固醇类抗炎药阿司匹林或吲哚美辛等。
本发明提供一种预防、减轻或治疗消化道疾病或消除炎症水肿的方法，所述方法包括对受试者给予本发明的化合物或其生理学上相容的盐。所述消化道疾病包括口腔、食道、胃肠疾病相关，所述口腔疾病包括口腔溃疡、口腔炎、牙龈炎、牙周炎等；所述食道疾病包括食管炎、食管溃疡等；所述胃肠疾病包括慢性胃炎、慢性萎缩性胃炎、急性胃炎、胃十二指肠溃疡、功能性胃肠道疾病、消化不良、癌前病变、消化系统肿瘤、胃肠道出血、胃食管返流疾病、急慢性肠炎、溃疡性结肠炎、克罗恩病和放化疗引起的黏膜损伤；但不限于此。在一实施方案中，所述消化道疾病的预防、减轻或治疗是通过调控干细胞增殖和分化进行的。所述方法通过本发明的化合物或其生理学上相容的盐对胃黏膜或肠黏膜等消化道黏膜起到保护作用或修复胃黏膜或肠黏膜等消化道黏膜的损伤，从而起到预防、减轻或治疗胃肠疾病的作用。
本发明提供一种修复黏膜或皮肤创面的方法，所述方法包括对受试者给予本发明的化合物或其生理学上相容的盐。
在上述本发明的方法中，本发明的化合物或其生理学上相容的盐是通过口服、注射、皮下等方式给药的。
第四方面，本发明提供一种药物、食品、保健品或化妆品、日用品组合物，所述组合物包括本发明的化合物或其生理学上相容的盐以及生理学上可接受的载体。在一实施方案中，所述生理学上可接受的载体包括药学上可接受的载体或化妆品可接受的载体。所述药物食品、保健品或化妆品、日用品组合物可以按照制剂学或化妆品常规技术制备，包括将作为活性成分的本发明的化合物与载体混合，按照常规技术制成所需要的剂型。可以根据需要，将本发明的组合物配制成口服施用制剂、黏膜施用制剂、注射制剂、吸入制剂和外用制剂。
本发明的多肽与已知多肽无同源性，便于人工多肽合成以获得高纯度多肽，与表皮生长因子多肽相比本发明的多肽仅由至多21个氨基酸残基组成，而且本发明的多肽口服给药后具有显著的消除炎症水肿、促进消化道黏膜损伤修复，减轻急慢性胃炎及消化道溃疡的胃肠疾病病理发展；具有促进皮肤创伤修复、缩短创面愈合时间、调解免疫功能等作用。口服给药也能发挥作用。此外，本发明的多肽用于体表皮肤创面时即使经碘制剂或双氧水消毒之后也能够起作用，而表皮生长因子用于体表皮肤时，经碘制剂或双氧水消毒之后结构会破坏，不能发挥作用。
具体实施方式
术语“生理学上相容的盐”是指生理学上相容的(即药理学上可接受的)并且对将被施用本发明化合物的个体基本上无毒的盐形式。本发明化合物的生理学上相容的盐包括由适宜的、无毒的有机或无机酸或无机碱形成的常规的和化学计量的酸加成盐或碱加成盐。
本领域技术人员应理解，本发明的皮肤创伤和/或黏膜损伤的修复可出于美容目的(即非治疗性目的)和治疗性目的施用。为此，本申请的术语“皮肤损伤”除了包括皮肤破损，烧伤、烫伤等，还包括出于美容目的修复的皮肤损伤例如，皱纹(例如紫外线照射导致的皱纹)、皮肤纹、裂缝、肿块、大毛孔(例如与附件结构如汗腺管、皮脂腺或毛囊相关的)，或不平或粗糙，皮肤失去弹性(功能性皮肤弹性蛋白丧失和/或失活)、下垂(包括眼部和下颌浮肿)、皮肤硬度丧失、皮肤紧实度丧失、皮肤变形后的回复能力丧失、变色(包括黑眼圈)、斑疱、肤色灰黄、色素过量皮肤区域例如老年斑和雀斑、角质物、异常的分化、过度角质化、弹性组织变性、胶原蛋白的破坏，以及皮肤角质，真皮，表皮层，皮肤血管系统(例如毛细血管扩张或多叉血管)，以及皮下组织，特别是靠近皮肤的皮下组织中的其它组织变化。
实施例
以下是结合具体试验对本发明的说明，并不是对本发明保护范围的限制。
实施例1：多肽的化学合成
多肽化合物的合成采用常规固相合成方法，经过树脂溶胀、取代、脱保护、洗涤、氨基酸溶解、氨基酸活化和缩合过程、洗涤、再脱保护多个循环过程，以及最后裂解和侧链脱保护。
实施例1：多肽的化学合成
多肽化合物的合成采用常规固相合成方法，经过树脂溶胀、取代、脱保护、洗涤、氨基酸溶解、氨基酸活化和缩合过程、洗涤、再脱保护多个循环过程，以及最后裂解和侧链脱保护。固相合成的反应方案如下所示：
表1.溶剂、试剂等的中英文缩写
合成实施例：
1)化合物1(Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu)全保护肽树脂的制备
(1)树脂溶胀：称取2-Chlorotrityl Chloride Resin 6.94g(SD＝0.65mmol/g)，加入到有筛板的合成管中，用100ml二氯甲烷(DCM)溶胀。
(2)制备Fmoc-Glu(OtBu)-树脂：按树脂、Fmoc-Glu(OtBu)-OH.H2O、DIPEA，以1:2:5.38的摩尔比分别称取Fmoc-Glu(OtBu)-OH.H2O、DIPEA，加入合成管中。室温N2鼓泡震荡1～3小时，抽干；然后分别用二甲基甲酰胺(DMF)洗涤5次，100ml/次，抽干树脂。
(3)脱除Fmoc保护基：向反应器中加入100ml的20％哌啶-DMF(v/v)溶液，N2鼓泡反应20min，抽干；然后用DMF洗涤5次，100ml/次，3分钟/次，抽干，茚三酮法检测Fmoc脱除结果。
(4)氨基酸预活化：在250ml烧杯中加入13.5mmol的Fmoc保护的氨基酸、13.5mmolHOBt、13.5mmol DIC，用100ml DMF溶解，室温下待用。
(5)氨基酸连接：将已活化的保护氨基酸溶液倒入反应器中，补加适量的DCM清洗用具。室温下N2鼓泡反应1～3小时，茚三酮法检测氨基酸连接是否完全，若完全，抽干。树脂用DMF洗涤5次，100ml/次，3min/次，抽干。每一种氨基酸、缩合剂的用量见表2。
(6)第一个氨基酸缩合完成后，重复步骤(4)和(5)，按照氨基酸顺序延长肽链至最后一个氨基酸偶联完毕。
(7)树脂肽用DMF洗涤4次，150ml/次，3min/次；再用DCM洗涤3次，150ml/次，3min/次，抽干。
表2.氨基酸、缩合剂的用量
2)切割
(1)在合成管中加入切割剂(TFA:TIS:H2O＝95:2.5:2.5，v/v)100ml，N2鼓泡反应1.5～3小时。
(2)切割反应完成后，将切割剂抽滤至250ml圆底烧瓶中。真空浓缩至原切割剂体积的四分之一后，加入10倍现有体积的甲基叔丁基醚，沉降得白色固体。将所得混合溶剂过滤，并用50ml甲基叔丁基醚分别清洗3次后，将所得粗肽产品置于砂芯漏斗在通风橱中N2吹干，使溶剂挥发至粗肽为粉末状。得到粗肽7.39g，粗产率89.0％。
3)纯化、换盐和冻干
(1)多肽HPLC纯化制备
A.色谱参数
色谱柱：动态轴向压缩柱80*250mm，填料：Daisogel C18(SP-100-8-ODS-P)
洗脱液A：10mM碳酸氢铵水溶液
洗脱液B：乙腈
流速：180ml/min
紫外检测波长：220nm
B.操作步骤
a)用水和/或乙腈溶解粗肽，并经0.45μm滤膜过滤
b)进样
c)乙腈-水流动相梯度洗脱
d)收集目标肽洗脱液
e)旋蒸浓缩
(2)多肽HPLC换盐(醋酸盐)
色谱参数
色谱柱：动态轴向压缩柱80*250mm，填料：Daisogel C18(SP-100-8-ODS-P)
洗脱液A1：0.1M乙酸
洗脱液A2：0.025M乙酸—0.1M乙酸铵洗脱液B：乙腈流速：180ml/min
紫外检测波长：220nm操作步骤a)95％A1+5％B平衡色谱柱b)进样
c)95％A2+5％B平衡色谱柱d)A1和B梯度洗脱e)收集目的肽洗脱液f)旋蒸浓缩g)冷冻干燥
表3.合成的化合物
注释：双电荷峰表示目标分子结合2个质子，三电荷峰表示目标分子结合3个质子；N/A代表称量有难度，未计实际重量。
化合物1：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C81H140N20O28；m/z：921.52014([M+2H]2+)，1842.03431([M+H]+).
1H NMR(600MHz,DMSO-d6)δ8.55(s,1H),8.46(s,2H),8.39(s,1H),8.14(s,6H),8.07–8.00(m,2H),7.98(d,J＝7.9Hz,1H),7.74(s,2H),7.60(s,1H),4.57(d,J＝7.9Hz,1H),4.47(d,J＝7.0Hz,1H),4.34–4.19(m,8H),4.18–4.09(m,4H),3.97–3.91(m,2H),3.85–3.79(m,1H),3.73(d,J＝11.8Hz,3H),3.68–3.55(m,7H),3.52(d,J＝5.7Hz,3H),3.43(t,J＝7.0Hz,1H),2.73(s,4H),2.21–2.09(m,4H),2.07–1.94(m,4H),1.92–1.64(m,19H,AcOH),1.63–1.38(m,16H),1.37–1.20(m,5H),1.01(d,J＝6.2Hz,3H),0.90–0.74(m,36H).
化合物2：Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C60H100N14O23；m/z：1385.72297([M+H]+).
1H NMR(600MHz,DMSO-d6)δ8.72(s,1H),8.34(s,1H),8.29(d,J＝7.3Hz,1H),8.17(s,1H),8.04(s,1H),8.02–7.93(m,5H),7.90(d,J＝8.8Hz,1H),7.51(d,J＝8.7Hz,1H),4.56(q,J＝7.6Hz,1H),4.42(q,J＝6.9Hz,1H),4.32–4.12(m,8H),4.08(q,J＝7.0Hz,1H),3.96–3.93(m,1H),3.82–3.71(m,4H),3.68–3.62(m,5H),3.51(d,J＝5.9Hz,3H),2.44–2.39(m,1H),2.23(dt,J＝8.0,4.2Hz,4H),2.06–1.85(m,8H,AcOH),1.84–1.39(m,14H),0.99(d,J＝6.3Hz,3H),0.89–0.78(m,31H).
化合物3：Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,DMSO-d6)δ8.52–8.33(m,3H),8.19(d,J＝8.1Hz,1H),8.10–7.87(m,6H),7.53(d,J＝8.8Hz,1H),4.60–4.51(m,2H),4.37–4.14(m,7H),4.11(t,J＝6.4Hz,1H),4.06(q,J＝7.1Hz,1H),3.97–3.90(m,1H),3.84–3.59(m,7H),3.54–3.42(m,6H),2.63–2.51(m,2H),2.22(t,J＝7.8Hz,4H),2.07–1.66(m,11H,AcOH),1.66–1.47(m,4H),1.42(t,J＝7.0Hz,2H),0.99(d,J＝6.3Hz,3H),0.90–0.72(m,24H).
化合物4：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu(醋酸盐)
1H NMR(600MHz,D2O)δ4.62–4.60(m,1H),4.40(t,J＝5.6Hz,1H),4.36(t,J＝7.2Hz,1H),4.32–4.24(m,2H),4.18–4.11(m,1H),4.01–3.94(m,2H),3.87–3.77(m,3H),2.97–2.92(m,4H),2.75–2.69(m,1H),2.60–2.53(m,1H),1.95–1.93(m,7H,AcOH),1.84–1.53(m,17H),1.46–1.33(m,4H),0.91–0.85(m,12H),0.82(t,J＝5.9Hz,6H).
化合物5：Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,DMSO-d6)δ8.45–8.41(m,1H),8.33–8.23(m,2H),8.04(t,J＝8.8Hz,2H),7.99(t,J＝6.0Hz,1H),7.85(d,J＝6.9Hz,1H),7.74(d,J＝8.8Hz,1H),4.58(q,J＝7.8Hz,1H),4.38–4.27(m,3H),4.27–4.21(m,3H),4.08–3.91(m,3H),3.84–3.79(m,1H),3.72–3.60(m,5H),3.56–3.47(m,4H),3.46(d,J＝5.0Hz,1H),2.22(q,J＝7.9Hz,4H),2.07–1.95(m,4H),1.95–1.77(m,8H,AcOH),1.76–1.69(m,1H),1.63–1.55(m,1H),1.45–1.38(m,2H),1.03(d,J＝6.2Hz,3H),0.90(d,J＝6.8Hz,3H),0.86–0.83(m,9H),0.80(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H).
化合物6：Leu-Pro-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C25H40N6O11；m/z：601.28438([M+H]+).
化合物7：Pro-Gly-Gly-Glu-Glu
1H NMR(600MHz,DMSO-d6)δ9.04(s,1H),8.50(d,J＝7.6Hz,1H),8.20(s,1H),7.85–7.79(m,1H),4.15(q,J＝7.2Hz,1H),3.93(q,J＝6.8Hz,1H),3.90–3.80(m,3H),3.79–3.57(m,3H),3.16–2.83(m,3H),2.23–2.05(m,6H),1.91–1.77(m,4H).
化合物8：Val-Thr-Val-Ser(醋酸盐)
1H NMR(600MHz,DMSO-d6+D2O+TFA)δ4.27(d,J＝5.7Hz,1H),4.25–4.22(m,1H),4.15(d,J＝6.6Hz,1H),3.91(p,J＝6.2Hz,1H),3.71–3.64(m,2H),3.63–3.59(m,1H),2.08–2.00(m,1H),1.96(h,J＝6.8Hz,1H),1.87(s,AcOH),1.04(d,J＝6.4Hz,3H),0.86(dd,J＝6.9,4.5Hz,6H),0.82–0.76(m,6H).
化合物9：Gly-Asp-Leu
1H NMR(600MHz,DMSO-d6+D2O+TFA)δ4.61(dd,J＝8.6,4.6Hz,1H),4.17–4.11(m,1H),3.59–3.49(m,2H),2.71–2.64(m,1H),2.56–2.49(m,1H),1.60–1.42(m,3H),0.82(d,J＝6.5Hz,3H),0.76(d,J＝6.5Hz,3H).
化合物10：Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu
高分辨质谱(TOF-HRMS)，分子式：C41H73N9O14；m/z：916.53883([M+H]+).
化合物11：Gly-Asp-Leu-Val-Thr-Val-Ser-Leu
高分辨质谱(TOF-HRMS)，分子式：C35H62N8O13；m/z：803.45303([M+H]+).
化合物12：Val-Thr-Val-Ser-Leu-Pro(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C28H50N6O9；m/z：615.37174([M+H]+).
1H NMR(600MHz,DMSO-d6+TFA)δ8.10(s,1H),7.97(d,J＝7.9Hz,1H),7.86(d,J＝8.1Hz,1H),7.71(d,J＝8.7Hz,1H),4.55(q,J＝7.9,7.5Hz,2H),4.32–4.23(m,2H),4.19(dd,J＝8.6,4.3Hz,1H),4.08(s,1H),3.98(td,J＝6.4,4.0Hz,1H),3.87(s,1H),3.65–3.58(m,2H),3.51(d,J＝5.9Hz,1H),3.44(s,2H),3.26(s,1H),3.18(d,J＝4.6Hz,1H),2.12–2.05(m,1H),2.03–1.93(m,3H),1.92–1.75(m,5H,AcOH),1.71–1.61(m,2H),1.52(s,1H),1.47–1.27(m,3H),1.01(d,J＝6.3Hz,3H),0.88–0.82(m,12H),0.80–0.78(m,6H).
化合物13：Val-Thr-Val-Ser-Leu
1H NMR(600MHz,DMSO-d6+D2O+TFA)δ4.28(dd,J＝7.3,5.4Hz,2H),4.19(dd,J＝9.7,5.2Hz,1H),4.14(d,J＝6.4Hz,1H),3.91(p,J＝6.2Hz,1H),3.67(d,J＝5.7Hz,1H),3.58–3.54(m,1H),3.53–3.48(m,1H),2.07–2.00(m,1H),1.98–1.92(m,1H),1.58–1.40(m,3H),1.04(d,J＝6.3Hz,3H),0.87(dd,J＝6.9,5.2Hz,6H),0.82–0.74(m,12H).
化合物14：Leu-Gly-Asp-Leu
高分辨质谱(TOF-HRMS)，分子式：C18H32N4O7；m/z：417.23391([M+H]+).
1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.55(d,J＝7.2Hz,1H),7.73(d,J＝7.8Hz,1H),4.37(q,J＝7.1Hz,1H),4.02(q,J＝7.5Hz,1H),3.91–3.80(m,1H),3.64–3.52(m,2H),2.54–2.49(m,1H),2.44–2.38(m,1H),1.66–1.57(m,2H),1.54–1.48(m,1H),1.48–1.37(m,3H),0.90–0.79(m,12H).
化合物15：Leu-Gly-Asp
高分辨质谱(TOF-HRMS)，分子式：C12H21N3O6；m/z：304.14925([M+H]+).
1H NMR(600MHz,DMSO-d6)δ8.69(s,1H),7.8711(d,J＝6.9Hz,1H),4.22–4.14(m,1H),3.78(d,J＝5.2Hz,2H),3.70(t,J＝7.2Hz,1H),2.46(d,J＝10.6Hz,1H),2.37–2.31(m,1H),1.70–1.63(m,1H),1.59–1.53(m,1H),1.51–1.45(m,1H),0.88(dd,J＝10.4,6.5Hz,6H).
化合物16：Leu-Lys-Ser-Lys(醋酸盐)
1H NMR(600MHz,DMSO-d6+D2O)δ4.35(t,J＝6.7Hz,1H),4.17–4.12(m,1H),3.66–3.60(m,1H),3.56–3.50(m,1H),3.31(d,J＝6.7Hz,1H),2.80–2.66(m,4H),1.84–1.45(m,19H,AcOH),1.45–1.11(m,7H),0.85–0.82(m,3H),0.80(d,J＝6.6Hz,3H).
化合物17：Leu-Lys-Ser-Lys-Leu(醋酸盐)
1H NMR(600MHz,DMSO-d6)δ8.53(d,J＝7.7Hz,1H),8.13(s,1H),7.87(d,J＝7.7Hz,1H),7.72(d,J＝7.8Hz,1H),4.34(s,1H),4.26(q,J＝6.1Hz,1H),4.21(q,J＝6.8Hz,1H),3.89(td,J＝8.4,5.1Hz,1H),3.64–3.49(m,2H),3.18(dd,J＝9.1,5.0Hz,1H),2.75–2.61(m,4H),1.86–1.58(m,12H,AcOH),1.57–1.15(m,14H),0.88–0.79(m,12H).
化合物18：Val-Thr-Val-Ser-Val-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C41H68N10O17；m/z：973.48858([M+H]+).
1H NMR(600MHz,DMSO-d6)δ8.62–8.50(m,2H),8.28(d,J＝8.0Hz,1H),8.11(d,J＝8.1Hz,1H),8.05(q,J＝9.1,7.5Hz,2H),7.77(d,J＝6.8Hz,1H),7.69(d,J＝8.8Hz,1H),4.36–4.29(m,3H),4.24–4.18(m,3H),4.05–3.85(m,4H),3.80–3.67(m,3H),3.59(d,J＝5.5Hz,1H),3.56–3.47(m,6H),2.25–2.16(m,4H),2.06–1.86(m,9H,AcOH),1.86–1.67(m,5H),1.03(d,J＝6.3Hz,3H),0.90(d,J＝6.9Hz,3H),0.86–0.73(m,16H).
化合物19：Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C39H64N10O17；m/z：945.45656([M+H]+).
1H NMR(600MHz,DMSO-d6)δ8.41–8.35(m,1H),8.32–8.26(m,1H),8.22(d,J＝7.5Hz,1H),8.04(d,J＝8.1Hz,1H),8.00(d,J＝7.5Hz,1H),7.97(t,1H),7.87(d,J＝6.9Hz,1H),7.76(d,J＝8.6Hz,1H),4.58–4.49(m,1H),4.31(s,1H),4.29–4.18(m,4H),4.06–4.00(m,1H),4.00–3.95(m,1H),3.81–3.75(m,1H),3.70–3.62(m,3H),3.60(s,1H),3.53(d,J＝5.8Hz,4H),3.45(d,J＝4.8Hz,1H),2.22(q,J＝7.3Hz,4H),2.07–1.74(m,14H,AcOH),1.74–1.67(m,1H),1.16(d,J＝6.8Hz,3H),1.03(d,J＝6.3Hz,3H),0.90(d,J＝6.9Hz,3H),0.84–0.77(m,9H).
化合物20:Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C40H68N10O17；m/z：961.48753([M+H]+).
化合物21：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O)δ4.45–4.26(m,10H),4.18–4.06(m,6H),4.01–3.91(m,6H),3.86–3.68(m,7H),3.64–3.57(m,1H),2.94(t,J＝7.6Hz,4H),2.70–2.65(m,1H),2.60–2.55(m,1H),2.37–2.21(m,5H),2.11–1.82(m,20H,AcOH),1.82–1.31(m,23H),1.12(d,J＝6.4Hz,3H),0.90–0.85(m,33H),0.82(d,J＝5.4Hz,3H).
化合物22：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O)δ4.63–4.54(m,4H),4.45–4.25(m,9H),4.16–4.08(m,4H),4.00–3.88(m,6H),3.85–3.70(m,6H),3.60(q,J＝7.4Hz,1H),2.94(t,J＝7.6Hz,4H),2.71–2.64(m,1H),2.63–2.57(m,1H),2.36–2.21(m,5H),2.11–1.86(m,15H,AcOH),1.86–1.46(m,18H),1.44–1.35(m,4H),1.33(d,J＝7.2Hz,3H),1.12(d,J＝6.3Hz,3H),0.90–0.84(m,27H),0.82(d,J＝5.6Hz,3H).
化合物23：Leu-Lys-Ser-Lys-Val-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O)δ4.95–4.72(m,7H),4.60(m,3H),4.44–4.30(m,7H),4.18–4.06(m,5H),4.02(d,J＝7.5Hz,1H),4.00–3.89(m,6H),3.88–3.68(m,6H),3.63–3.56(m,1H),2.93(t,J＝7.8Hz,4H),2.71–2.66(m,1H),2.62–2.56(m,1H),2.39–2.29(m,4H),2.26–2.21(m,1H),2.11–1.84(m,29H,AcOH),1.83–1.74(m,2H),1.74–1.48(m,12H),1.44–1.30(m,4H),1.11(d,J＝6.4Hz,3H),0.90–0.84(m,36H).
化合物24：Leu-Lys-Ser-Lys-Ala-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O)δ4.46–4.22(m,10H),4.17–4.09(m,4H),4.01–3.83(m,8H),3.81–3.70(m,4H),3.63–3.57(m,1H),2.97–2.92(m,4H),2.71–2.66(m,1H),2.65–2.59(m,1H),2.37–2.21(m,5H),2.12–1.85(m,16H,AcOH),1.84–1.48(m,14H),1.45–1.31(m,10H),1.13(d,J＝6.4Hz,3H),0.91–0.85(m,24H).
化合物25：Leu-Lys-Ser-Lys-Ile-Gly-Asp-Ile-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C81H140N20O28；m/z：921.51833([M+2H]2+)，1842.02826([M+H]+).1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.63–4.53(m,3H),4.37–4.18(m,8H),4.17–4.08(m,4H),4.00(d,J＝7.3Hz,1H),3.97–3.91(m,1H),3.80–3.57(m,8H),3.55–3.42(m,4H),2.84(s,1H),2.76–2.64(m,6H),2.58–2.51(m,1H),2.25(q,J＝9.4,7.6Hz,4H),2.10–2.00(m,1H),1.99–1.59(m,23H,AcOH),1.59–1.44(m,10H),1.42–1.20(m,7H),1.05–0.90(m,5H),0.85–0.68(m,36H).
化合物26：Leu-Arg-Ser-Arg-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C33H61N9O11；m/z：633.35164([M+3H]3+)，1898.04261([M+H]+).
化合物27：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C79H138N20O28；m/z：606.00885([M+3H]3+)，1816.01835([M+H]+).
化合物28：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Gly-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C78H136N20O28；m/z：601.33780([M+3H]3+)，1802.01155([M+H]+).
化合物29：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Ala-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C76H132N20O28；m/z：591.99278([M+3H]3+)，1773.96555([M+H]+).
化合物30：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Asp
高分辨质谱(TOF-HRMS)，分子式：C80H138N20O28；m/z：610.00844([M+3H]3+)，1828.01427([M+H]+).
化合物31：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val1-3Thr-Val-Ser-Leu-Pro-Gly-Gly-Gln-Glu
高分辨质谱(TOF-HRMS)，分子式：C81H141N21O27；m/z：921.02784([M+2H]2+).
化合物32：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C81H141N21O27；m/z：921.02807([M+2H]2+).
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.88–4.73(m,6H),4.55–4.45(m,2H),4.31–4.25(m,3H),4.23–4.01(m,9H),3.99–3.93(m,1H),3.82–3.50(m,12H),3.45(s,1H),2.78–2.67(m,5H),2.66–2.59(m,1H),2.27(t,J＝7.9Hz,2H),2.19–2.11(m,2H),2.11–1.72(m,16H,AcOH),1.71–1.17(m,26H),0.98(d,J＝6.3Hz,3H),0.81–0.73(m,30H),0.71(t,J＝7.0Hz,6H).
化合物34：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly(醋酸盐)
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.57–4.44(m,3H),4.35–4.21(m,7H),4.19–4.15(m,1H),4.11(q,J＝4.6,3.9Hz,2H),4.07(d,J＝7.5Hz,1H),4.00–3.93(m,1H),3.83–3.46(m,11H),2.80–2.69(m,5H),2.67–2.60(m,1H),2.10–1.75(m,13H,AcOH),1.74–1.20(m,26H),0.99(d,J＝6.3Hz,3H),0.83–0.75(m,30H),0.72(dd,J＝9.1,6.1Hz,6H).
化合物35：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly(醋酸盐)
1H NMR(600MHz,D2O)δ4.62-4.49(m,4H),4.44–4.33(m,4H),4.33–4.24(m,4H),4.15–4.07(m,3H),4.00–3.66(m,12H),3.64–3.56(m,1H),2.94(t,J＝7.7Hz,4H),2.68–2.62(m,1H),2.59–2.51(m,1H),2.28–2.21(m,1H),2.07–1.49(m,32H,AcOH),1.45–1.33(m,4H),1.12(d,J＝6.3Hz,3H),0.90–0.85(m,30H),0.81(t,J＝6.6Hz,6H).
化合物36：Leu-Lys-Ser-Lys-Leu-Gly-Glu-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O)δ4.52–4.23(m,11H),4.15–4.08(m,4H),4.00–3.87(m,6H),3.86–3.67(m,6H),3.63–3.56(m,1H),2.96–2.91(m,4H),2.35–2.19(m,7H),2.11–1.46(m,40H,AcOH),1.44–1.32(m,4H),1.11(d,J＝6.4Hz,3H),0.90–0.84(m,30H),0.81(t,J＝6.3Hz,6H).
化合物37：Leu-Lys-Ser-Lys-Leu-Gly-Asn-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O+TFA)δ4.48(s,1H),4.43(d,J＝8.4Hz,1H),4.28–4.13(m,8H),4.10(d,J＝6.0Hz,2H),4.00–3.92(m,3H),3.82–3.51(m,12H),3.42(s,1H),2.80–2.71(m,5H),2.60–2.55(m,1H),2.54–2.47(m,1H),2.45(s,3H),2.25(t,J＝7.2Hz,4H),2.10–1.29(m,39H,AcOH),1.21(s,4H),0.94(d,J＝6.4Hz,3H),0.74–0.68(m,30H),0.64(t,J＝6.1Hz,6H).
化合物39：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.37–4.11(m,13H),3.96(dd,J＝6.4,4.5Hz,1H),3.79–3.47(m,13H),2.77–2.63(m,5H),2.29–2.20(m,4H),2.11–1.21(m,42H,AcOH),1.15(d,J＝6.8Hz,3H),0.98(d,J＝6.3Hz,3H),0.86–0.76(m,30H).
化合物40：Val-Lys-Thr-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C81H140N20O28；m/z：921.52020([M+2H]2+)，1842.0936([M+H]+).
化合物41：Val-Lys-Thr-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C80H138N20O28；m/z：610.00824([M+3H]3+)，914.51043([M+2H]2+)，1828.01136([M+H]+).
化合物42：Ala-Lys-Ala-Lys-Ala-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C75H128N20O27；m/z：871.47546([M+2H]2+).
化合物43：Val-Lys-Ala-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu
高分辨质谱(TOF-HRMS)，分子式：C79H136N20O27；m/z：600.00616([M+3H]3+)，899.50814([M+2H]2+)，1798.00999([M+H]+).
化合物44：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Asp-Asp(醋酸盐)
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.61–4.45(m,4H),4.36–4.16(m,11H),3.80–3.74(m,3H),3.71–3.65(m,6H),3.64–3.56(m,3H),3.53–3.45(m,4H),2.77–2.61(m,7H),2.59–2.51(m,1H),2.46–2.41(m,1H),2.08–1.76(m,11H),1.73–1.14(m,26H),0.97(d,J＝6.3Hz,3H),0.88–0.76(m,36H).
化合物45：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Asp-Asp(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C81H140N20O28；m/z：614.68030([M+3H]3+)，921.51901([M+2H]2+)，1842.02875([M+H]+).
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.56–4.46(m,4H),4.37–4.10(m,23H),3.77(t,J＝7.3Hz,1H),3.67(s,2H),3.62–3.56(m,2H),3.53–3.44(m,4H),2.77–2.54(m,8H),2.47–2.44(m,1H),2.07–1.74(m,15H,AcOH),1.73–1.14(m,31H),0.97(d,J＝6.3Hz,3H),0.88–0.76(m,36H).
化合物46：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Gln-Gln
高分辨质谱(TOF-HRMS)，分子式：C83H146N22O26；m/z：623.36767([M+3H]3+)，1868.08748([M+H]+).
化合物47：Leu-Lys-Ser-Lys-Leu-Pro-Val-Pro-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.53(t,J＝7.1Hz,1H),4.49–4.44(m,1H),4.41–4.12(m,16H),3.79–3.41(m,18H),2.72(q,J＝7.6Hz,4H),2.28–2.20(m,4H),2.06–1.23(m,50H,AcOH),0.98(d,J＝6.3Hz,3H),0.88–0.76(m,36H).
化合物48：Leu-Lys-Ser-Lys-Leu-Ala-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.52(q,J＝7.1Hz,2H),4.35–4.12(m,15H),3.79–3.56(m,9H),3.52–3.44(m,4H),2.76–2.65(m,5H),2.29–2.20(m,4H),2.07–1.23(m,40H,AcOH),1.18(d,J＝7.1Hz,3H),0.97(d,J＝6.3Hz,3H),0.88–0.73(m,36H).
化合物49：Leu-Lys-Ser-Lys-Leu-Ala-Glu-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O+DMSO-d6+TFA)δ4.54-4.47(m,1H),4.31–4.10(m,14H),3.95(dd,J＝6.4,4.4Hz,1H),3.78–3.56(m,7H),3.54–3.42(m,4H),2.85(s,1H),2.76–2.70(m,4H),2.69(s,1H),2.29–2.12(m,6H),2.07–1.23(m,43H,AcOH),1.18(d,J＝7.1Hz,3H),0.97(d,J＝6.3Hz,3H),0.86–0.74(m,36H).
化合物50：Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O+TFA)δ4.49–4.45(m,1H),4.31–4.18(m,5H),4.04(d,J＝8.2Hz,1H),3.99(d,J＝7.3Hz,1H),3.95(dd,J＝6.5,5.4Hz,1H),3.88(t,J＝7.4Hz,1H),3.82–3.72(m,4H),3.67–3.55(m,3H),3.48–3.42(m,1H),2.33–2.26(m,4H),2.14–1.70(m,15H,AcOH),1.58–1.31(m,5H),0.97(d,J＝6.4Hz,3H),0.77–0.69(m,24H).
化合物51：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Val-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C81H142N20O28；m/z：615.35313([M+3H]3+)，922.52805([M+2H]2+)，1844.05005([M+H]+).
化合物52：Lys-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C87H152N22O29；m/z：657.38043([M+3H]3+)，1970.13025([M+H]+).1H NMR(600MHz,D2O)δ4.64–4.53(m,6H),4.45–4.23(m,11H),4.16–4.08(m,4H),3.99–3.87(m,6H),3.85–3.69(m,6H),3.64–3.56(m,1H),2.97–2.92(m,6H),2.70–2.64(m,1H),2.61–2.54(m,1H),2.35–2.21(m,5H),2.12–1.73(m,23H,AcOH),1.73–1.49(m,20H),1.45–1.33(m,6H),1.12(d,J＝6.4Hz,3H),0.89–0.80(m,36H).
化合物53：Pro-Val-Pro-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
1H NMR(600MHz,D2O)δ4.62–4.53(m,6H),4.47–4.22(m,15H),4.16–4.08(m,4H),3.97–3.87(m,5H),3.86–3.69(m,7H),3.66–3.56(m,2H),3.42–3.29(m,2H),2.97–2.89(m,4H),2.70–2.64(m,1H),2.62–2.54(m,1H),2.44–2.18(m,7H),2.11–1.72(m,27H,AcOH),1.71–1.47(m,19H),1.43–1.31(m,4H),1.11(d,J＝6.4Hz,3H),0.95(d,J＝6.7Hz,3H),0.90–0.79(m,42H).
化合物54：Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C75H129N19O27；m/z：864.97732([M+2H]2+)，1728.94810([M+H]+).1H NMR(600MHz,D2O+CD3OD)δ4.61–4.48(m,5H),4.45–4.35(m,2H),4.32–4.22(m,5H),4.21–4.16(m,1H),4.12–4.04(m,4H),3.96(t,J＝6.7Hz,1H),3.92–3.64(m,11H),3.58–3.51(m,1H),2.90(q,J＝7.7Hz,4H),2.68–2.60(m,1H),2.59–2.52(m,1H),2.33–2.14(m,5H),2.06–1.28(m,40H,AcOH),1.07(d,J＝6.4Hz,3H),0.85–0.75(m,31H).
化合物55：Leu-Lys-Ser-Lys-Leu-Gly-Asp(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C33H61N9O11；m/z：380.73248([M+2H]2+)，760.45776([M+H]+).
1H NMR(600MHz,D2O)δ4.44–4.25(m,5H),4.01–3.93(m,2H),3.88–3.75(m,3H),2.94(q,J＝7.3Hz,4H),2.73–2.65(m,1H),2.62–2.53(m,1H),1.94(s,8H,AcOH),1.84–1.50(m,14H),1.46–1.31(m,4H),0.92–0.85(m,9H),0.82(d,J＝5.4Hz,3H).
实施例2多肽化合物1及其相关多肽对HaCAT细胞增殖的促进作用
实验方法:将人永生化角质形成细胞(HaCaT细胞)浓度调整为1.0×105～5.0×105/mL进行传代培养，于37℃，5％CO2条件下培养24～36小时后用于生物学活性检测。用胰酶消化并收集细胞，用无血清培养基配成浓度2.5×104/mL接种于96孔细胞培养板中，每孔100μL，于37℃，5％CO2条件下培养过夜。再加入50μL用无血清培养基配制的不同浓度多肽化合物溶液，使待测多肽化合物终浓度为0.2ug/mL；同时设置EGF对照组，即加入50μL用无血清培养基配制的重组人表皮生长因子(EGF)溶液，终浓度为100ng/mL；模型对照组，即加入等体积的无血清培养基。于37℃，5％CO2条件下培养72小时，采用CellTiter-试剂盒检测HaCaT细胞株增殖情况。
结果：试验结果统计分析见表4。多肽化合物1及其相关多肽促进HaCaT细胞增殖的效果具有强弱差异性。其中多肽H308无促增殖作用，而其它多肽都具有显著促增殖作用，说明多肽化合物1及其相关多肽在皮肤相关疾病方面具有潜在的应用价值。
表4多肽对HaCaT细胞的促增殖作用
注：
－表示无促增殖作用；
以空白对照组的增殖率为100％计算，+代表增殖率为120～150％；++代表增殖率为150～200％；+++代表增殖率为200～250％；++++代表增殖率为250～300％
实验例3多肽化合物1在急性机械损伤动物模型上的创面修复作用
将SPF级SD大鼠(体重180～230g)分别饲养于干净消毒笼内，每天定时给予水、饲料和更换垫料，保持饲养温度22℃，湿度55％～65％，饲养一周使其适应环境。大鼠用3％戊巴比妥钠腹腔注射麻醉成功后，剪去创口边缘1cm处毛发，先用碘伏消毒创口区，再用75％的酒精局部消毒创口区，于耳连线中间向背部下4cm近颈侧以脊柱为中线位制作1.5cm×1.5cm(即直径是1.5cm)圆形全层皮肤创口，深至肌层。用橡胶圈固定其周围皮肤，形成急性机械性损伤动物模型。造模后大鼠伤口暴露，单笼饲养。设置模型对照组(生理盐水)、EGF对照组(商品名：金因肽)、化合物1治疗组(高低剂量，浓度分别为2、0.4mg/mL)，每组6只。换药时均先用碘伏清创，再以无菌生理盐水冲洗创面并拭干。每日定时局部给药1次，于创面滴加35μL，持续给药14+天。
每天进行1次体重监测以及创面观察(包括创面有无红肿、渗出液及有无感染，创口收缩、表面结痂、新生表皮的情况)。得到结果如下：
(1)本研究过程对大鼠体重进行定期监测，结果显示大鼠的体重处于正常生长的状态，各组别的大鼠体重无显著差异性。
(2)在建模后的第0、10、14天，摄取每组大鼠的创面图像，采用图像分析软件(Image J)计算创面面积，根据公式，进而得出创面愈合率。最后用统计分析软件分析各组愈合率有无统计学意义。创面愈合率结果如表5所示。
表5创面愈合率(％)
| 组别 | 给药第0天 | 给药第10天 | 给药第14天 |
| 模型对照组 | 0.00±0.00 | 13.51±7.20 | 61.96±7.55 |
| EGF对照组 | 0.00±0.00 | 26.52±9.46 | 72.88±2.63 |
| 化合物1低剂量组 | 0.00±0.00 | 35.99±2.47 | 73.79±6.51 |
| 化合物1高剂量组 | 0.00±0.00 | 35.60±6.54 | 84.20±1.00* |
注：*表示与模型对照组相对，P<0.05
表5结果显示与模型对照组相比，多肽化合物1的高剂量组具有显著促创面愈合的效果(P<0.05)。
实施例4新多肽化合物1对小鼠皮肤创伤的修复作用
试验方法：选取60只8～10周雄性昆明小鼠(购自北京斯贝福生物技术有限公司)分笼饲养，自由取食，试验前一天停止进食。用0.2ml质量分数1％戊巴比妥钠腹腔注射麻醉小鼠，背部剪毛，脊柱表皮皮肤上下对称开0.5cm*0.5cm正方形伤口，剪去全层皮肤，勿伤及肌肉层，伤口止血备用。次日，用乙醚麻醉小鼠，伤口处滴加不同溶液浓度的化合物1(0.15mg/ml或0.30mg/ml)、生理盐水和康复新液各0.1ml，每日换药一次，在4、7、11天观察创面愈合情况。按照公示计算创面愈合率：创面愈合率(％)＝(原始创面面积-未愈合创面面积)/原始创面面积。结果见表6。
表6小鼠创伤愈合率统计结果
注：与模型组相比，*P<0.05有显著性差异
试验结果表明，新多肽化合物1能够明显促进小鼠皮肤创伤的愈合，与对照组比较具有显著性差异，且优于康复新液。
实施例5：实施例1获得的部分多肽样品对乙醇诱导的小鼠胃溃疡模型的抗溃疡作用
1、实验动物：SPF级C57BL/6小鼠，成都药康生物科技有限公司，动物许可证号：SCXK(川)2020-034
2、方法：
实验动物适应性喂养后，实验前1天给药后所有动物开始禁食不禁水24h。造模前实验小鼠随机分组：空白组5只、模型组10只、替普瑞酮组10只、各多肽化合物给药组10只，除空白组及模型组灌胃给予纯化水以外，替普瑞酮组按照160mg/kg灌胃，多肽给药组均按照0.2mg/kg灌胃给予不同受试样品，给药1小时后，各组小鼠经口灌胃给予0.9ml/kg的无水乙醇造模，1h后利用脱颈法处死动物，结扎胃贲门和夹闭幽门，摘取全胃。向胃体内注入1％甲醛溶液1mL，结扎贲门，取出胃后即放入1％甲醛溶液中。浸泡30min后取出胃组织，沿胃大弯剪开，使用生理盐水冲洗干净胃内容物，平铺后观察并测定小鼠胃黏膜的损伤，计算溃疡指数和溃疡抑制率，并拍摄胃全景照片。
溃疡指数计算方法：条索状损伤长度大于1mm者，测量其长度，每毫米计1分；若其宽度大于1mm，将计分按宽度的毫米数加倍；长度小于1mm计0.5分，将计分相加得出该动物的溃疡指数。
溃疡抑制率％＝(模型组溃疡指数-给药组溃疡指数)/模型组溃疡指数×100％；
相对溃疡抑制率＝(测试化合物溃疡抑制率)/(化合物1溃疡抑制率)。
3、结果：表7示出了本发明化合物的相对溃疡抑制率：
表7本发明化合物的相对溃疡抑制率
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*注释：
系列化合物的抗溃疡作用经多批试验完成，为便于比较活性以相对溃疡抑制率表示。
溃疡指数高于模型组的为阴性，表示为“-”；溃疡指数低于模型组的为阳性，表示为“+”。
每批试验都以化合物1作为对照组，设化合物1的相对溃疡抑制率为1，表示为“+++”；
相对溃疡抑制率>1.20，表示为“++++”；
相对溃疡抑制率为0.9-1.20，表示为“+++”；
相对溃疡抑制率为0.6–0.9，表示为“++”；
相对溃疡抑制率为0.3–0.6，表示为“+”；
相对溃疡抑制率<0.3，表示为“/”(极低活性)。
实施例6新多肽化合物1对大鼠应激性胃溃疡的治疗作用
试验方法：选取75只体重180～210g雄性SD大鼠(购自北京斯贝福生物技术有限公司)，分笼适应性饲养1周后，随机分空白组、模型组、硫糖铝组(1g/kg，阳性药组)、化合物1低剂量组(1.5mg/kg)和高剂量组(3.0mg/kg)。给药组灌胃给药。造模前一天禁食不禁水，除对照组外，采用束缚水浸法造模，将各组大鼠固定于鼠板，头向上垂直浸泡在温度为20℃的恒温水槽中8小时，水面与大鼠剑突齐平。应激造模结束后，将大鼠颈椎脱臼处死，剖腹，结扎幽门。向胃内灌注2ml体积分数为10％甲醛溶液，结扎贲门，取出胃体至于甲醛溶液中固定15分钟。沿胃大弯剪开，生理盐水冲洗后展开，观察胃黏膜损失并计算胃溃疡指数。按照Guth标准计算溃疡指数(UI)：点状出血计为1分，线状出血长度<1mm为2分，2～4mm为4分，>4mm为5分，宽度>1mm时分值*2。结果见表8。
表8大鼠胃溃疡指数统计结果
注：与模型组相比，*P<0.01有显著性差异
试验结果表明，新多肽化合物1对大鼠应激性胃溃疡具有明显的保护作用，与模型组比较具有显著性差异，其保护效果优于阳性药硫糖铝。
实施例7部分多肽样品的胃、肠稳定性试验和消毒剂处理后稳定性
方法：取待测样品(化合物1、化合物2、化合物3、化合物5、化合物18、化合物19及对照品EGF))各1mg，加水1ml溶解。取样品溶液100ul，加水900ul，混匀，作为对照品溶液。取样品溶液各100ul，分别加人工胃液(W)、人工肠液(X)、聚维酮碘溶液(I)、过氧化氢溶液(O)900ul，37℃恒温水浴1小时，放冷，滤过，作为供试品溶液，用高效液相色谱法分别检测处理前及处理后的样品峰面积,试验结果以样品的峰面积进行对比计算。以水稀释后不做任何处理的原液作为对照，对比统计其他供试品溶液相应位置的峰面积(含量)变化情况。
表9多肽样品的胃、肠,体外消毒剂处理后稳定性试验
| 编号 | W保留％ | X保留％ | I保留％ | O保留％ |
| EGF | 0 | 0 | 0 | 0 |
| 化合物1 | 0 | 0 | 106 | 104 |
| 化合物2 | 0 | 56 | 99 | 99 |
| 化合物3 | 0 | 63 | 101 | 99 |
| 化合物5 | 99 | 100 | 98 | 100 |
| 化合物18 | 99 | 100 | 99 | 100 |
| 化合物19 | 101 | 100 | 99 | 98 |
注：W表示人工胃液，X表示人工肠液，I表示聚维酮碘溶液，O表示过氧化氢溶液
结果：如表9所示，供试品化合物1、2、3、5、18、19的样品在聚维酮碘溶液(I)和过氧化氢溶液(O)都100％保留，说明可以和消毒剂共同使用，消毒处理后很稳定；化合物5、18、19对人工胃液(W)、人工肠液(X)也稳定21，化合物2、3对人工肠液(X)也有一定的稳定性；EGF在胃液和肠液里都没有保留，说明在胃液和肠液中不稳定，聚维酮碘溶液和过氧化氢溶液消毒后涂抹EGF外用也会被破坏。
尽管本发明披露了上述实施例，但本发明的实施方式并不限于上述实施例，其他的任何未背离本发明的改变、修饰、替代、组合、简化，均应为等效的置换方式均包含在本发明的保护范围之内。
序列表
<110> 四川好医生攀西药业有限责任公司
<120> 用于修复皮肤创伤或黏膜损伤的多肽及其应用
<130> F21W0973PCT
<141> 2021-08-26
<150> CN 202010873377.3
<151> 2020-08-26
<160> 55
<170> SIPOSequenceListing 1.0
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<213> 人工序列(Artificial Sequence)
<400> 26
Leu Arg Ser Arg Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 27
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Ala Gly Gly
1 5 10 15
Glu Glu
<210> 28
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Gly Gly Gly
1 5 10 15
Glu Glu
<210> 29
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Ala Ala Gly Gly
1 5 10 15
Glu Glu
<210> 30
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Asp
<210> 31
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Gln Glu
<210> 32
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Gln
<210> 33
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10
<210> 34
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly
1 5 10 15
<210> 35
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
<210> 36
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Leu Lys Ser Lys Leu Gly Glu Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 37
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Leu Lys Ser Lys Leu Gly Asn Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 38
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Leu Lys Ser Lys Leu Pro Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 39
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Ala Pro Gly Gly
1 5 10 15
Glu Glu
<210> 40
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Val Lys Thr Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 41
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Val Lys Thr Lys Val Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 42
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Ala Lys Ala Lys Ala Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 43
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Val Lys Ala Lys Val Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 44
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Asp Asp
<210> 45
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Ala Ala
1 5 10 15
Asp Asp
<210> 46
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Ala Ala
1 5 10 15
Gln Gln
<210> 47
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Leu Lys Ser Lys Leu Pro Val Pro Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 48
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Leu Lys Ser Lys Leu Ala Asp Val Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 49
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Leu Lys Ser Lys Leu Ala Glu Val Val Thr Val Ser Leu Pro Gly Gly
1 5 10 15
Glu Glu
<210> 50
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Leu Val Thr Val Ser Leu Pro Gly Gly Glu Glu
1 5 10
<210> 51
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Val Gly Gly
1 5 10 15
Glu Glu
<210> 52
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Lys Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly
1 5 10 15
Gly Glu Glu
<210> 53
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Pro Val Pro Leu Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu
1 5 10 15
Pro Gly Gly Glu Glu
20
<210> 54
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Lys Ser Lys Leu Gly Asp Leu Val Thr Val Ser Leu Pro Gly Gly Glu
1 5 10 15
Glu
<210> 55
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Leu Lys Ser Lys Leu Gly Asp
1 5
Claims (4)
1.化合物或其生理学上相容的盐，其中所述化合物选自：
Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu；
Lys-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu。
2.权利要求1所述的化合物或其生理学上相容的盐在制备用于修复皮肤创伤或预防胃溃疡的药物中的用途。
3.根据权利要求2的用途，其中所述皮肤创伤与表皮炎症、机械及手术创面、烧伤及烫伤、溃疡、瘘管、褥疮、放化疗引起的皮肤损伤的疾病相关。
4.一种药物组合物，所述组合物包括权利要求1中的化合物或其生理学上相容的盐以及生理学上可接受的载体。
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| CN2020108733773 | 2020-08-26 | ||
| CN202010873377 | 2020-08-26 |
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| CN114106100B true CN114106100B (zh) | 2024-05-17 |
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| Country | Link |
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| CN (1) | CN114106100B (zh) |
| TW (1) | TW202207967A (zh) |
| WO (1) | WO2022042590A1 (zh) |
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| CN107667112A (zh) * | 2015-05-26 | 2018-02-06 | 珍白斯凯尔有限公司 | 新型肽和含有其的组合物 |
| CN108530527A (zh) * | 2018-04-23 | 2018-09-14 | 昆明医科大学 | 一种多肽oa-gl21及其提纯方法与应用 |
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| JP2982078B2 (ja) * | 1990-10-05 | 1999-11-22 | アース製薬株式会社 | イヌ上皮細胞成長因子、該イヌ上皮細胞成長因子を有効成分とする抗炎症剤又は化粧料、及び該イヌ上皮細胞成長因子ｃＥＧＦの製造方法 |
| CN102657845B (zh) * | 2012-05-31 | 2013-09-11 | 中国科学院昆明动物研究所 | 无指盘臭蛙促皮肤修复多肽ah90和cw49的应用 |
| EP3229826A4 (en) * | 2014-12-09 | 2018-08-15 | The Regents of The University of California | Methods of promoting tissue healing and repair |
| CN108586575B (zh) * | 2018-04-11 | 2020-08-14 | 福建省中科生物股份有限公司 | 一种多肽及其皮肤修复功能的应用 |
| CN108586576B (zh) * | 2018-04-23 | 2019-07-12 | 昆明医科大学 | 一种多肽oa-ff10及其提纯方法与应用 |
| CN109320591B (zh) * | 2018-10-26 | 2021-06-01 | 昆明医科大学 | 一种多肽oa-gl12及其应用 |
| CN110642924B (zh) * | 2019-10-12 | 2022-10-28 | 杨莹 | 一种皮肤保护肽om-tv16及其制备方法与应用 |
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- 2021-08-25 CN CN202110984908.0A patent/CN114106100B/zh active Active
- 2021-08-25 WO PCT/CN2021/114499 patent/WO2022042590A1/zh active Application Filing
- 2021-08-25 TW TW110131495A patent/TW202207967A/zh unknown
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| WO2022042590A1 (zh) | 2022-03-03 |
| TW202207967A (zh) | 2022-03-01 |
| CN114106100A (zh) | 2022-03-01 |
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