WO2022016375A1 - 异位子宫内膜识别多肽及其衍生物和应用 - Google Patents

异位子宫内膜识别多肽及其衍生物和应用 Download PDF

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WO2022016375A1
WO2022016375A1 PCT/CN2020/103288 CN2020103288W WO2022016375A1 WO 2022016375 A1 WO2022016375 A1 WO 2022016375A1 CN 2020103288 W CN2020103288 W CN 2020103288W WO 2022016375 A1 WO2022016375 A1 WO 2022016375A1
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polypeptide
recognition
ectopic endometrial
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张键
赵华山
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Shenzhen Institute of Advanced Technology of CAS
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  • the invention belongs to the field of medical cell biology, and relates to an ectopic endometrial recognition polypeptide and its derivatives and applications.
  • Endometriosis is a gynecological disease formed by the attachment and growth of active cells in the endometrial tissue outside the body's endometrium. Studies estimate that as of 2015, more than 10 million people worldwide were affected. About 6-10% of women are affected by it. The most common sites of disease are the ovaries, fallopian tubes, and the tissues surrounding the uterus and ovaries. The main symptoms are pelvic pain and infertility. The cause of its pathogenesis is not fully understood. The endometriosis area can ooze blood leading to inflammation and scarring. Diagnosis is usually based on symptoms combined with medical imaging, with biopsy being the most reliable method of diagnosis. There is no cure for endometriosis, but many treatments can improve its symptoms. Endometriosis is often misdiagnosed due to the lack of specific diagnostic markers. Therefore, it is extremely valuable to find specific diagnostic identifiers for this intractable disease.
  • the purpose of the present invention is to provide an ectopic endometrial recognition polypeptide and its derivatives and applications.
  • One aspect of the present invention provides an ectopic endometrial recognition polypeptide, comprising a combination of one or more of the following sequences,
  • the purity of the polypeptide is 50-100%.
  • the purity of the polypeptide is 90-95%.
  • Another aspect of the present invention provides a derivative of any of the above-mentioned ectopic endometrial-recognition polypeptides, wherein the derivative is a product obtained by modifying the terminal or side chain of the ectopic endometrial-recognition polypeptide, Or the product obtained by the labeling and modification of the ectopic endometrial recognition polypeptide with the fluorescent group, or the product obtained by the isotopic labeling of the ectopic endometrial recognition polypeptide, or the product obtained by the phosphorylation modification of the ectopic endometrial recognition polypeptide, Or the product obtained by cyclization modification based on disulfide bond of ectopic endometrial recognition polypeptide, or the product obtained by biotin labeling of ectopic endometrial recognition polypeptide, or the modification of ectopic endometrial recognition polypeptide by photosensitizer
  • terminal or side chain modification of the ectopic endometrial recognition polypeptide includes but is not limited to N-terminal acetylation modification and C-terminal amination modification.
  • the fluorescent dyes used in the labeling modification of the fluorescent group by the ectopic endometrial recognition polypeptide include but are not limited to FITC, Rhodamine, Cy3, Cy5, Cy5.5, Cy7, and the modification is used for the purpose of fluorescence detection. .
  • polypeptide identified ectopic endometrial isotopically labeled isotopically used include, but are not limited to 13 C, the modified for tracking purposes.
  • the phosphorylation modification of the ectopic endometrial recognition polypeptide includes but is not limited to p-Ser, p-Thr, and p-Tyr.
  • the ectopic endometrial recognition polypeptide is labeled with biotin for the purpose of localization detection and the like.
  • the ectopic endometrial recognition polypeptide is modified with a photosensitizer, so as to facilitate the preparation of a photosensitizer.
  • the ectopic endometrial recognition polypeptide is modified with azide, which is beneficial to the secondary ligation reaction.
  • the ectopic endometrial recognition polypeptide is PEG-modified for preparation of a drug carrier.
  • the ectopic endometrial recognition polypeptide can be synthesized independently by general organic chemistry laboratory conditions, or industrially synthesized by conventional commercial reagent companies, that is, the polypeptide is synthesized by the solid-phase method, and the condensation reaction between different amino acids on the resin can be carried out. Achieves the synthesis of directional amino acid chains.
  • the desired modification group is applied after the amino acid is linked.
  • Another aspect of the present invention provides the use of any one of the above-mentioned polypeptides or any of the above-mentioned derivatives in the preparation of a medicament for diagnosing and/or treating endometriosis.
  • Another aspect of the present invention provides a pharmaceutical composition for diagnosing and/or treating endometriosis, comprising any of the above-mentioned polypeptides or any of the above-mentioned derivatives.
  • the ectopic endometrial recognition polypeptide and its derivatives can be combined with conventional organic chemical methods on a diagnostic and/or therapeutic carrier to exert application value based on the specific recognition function, thereby obtaining disease intervention tools that can be used for diagnosis and treatment.
  • polypeptide probe adopts any of the above-mentioned polypeptide sequences or any of the above-mentioned derivatives, and reacts it with a fluorescent dye through conventional organic chemistry (such as EDC method reaction ligation) combined.
  • the fluorescent dyes are selected from dyes with fluorescent groups in the near-infrared region, preferably, the dyes with fluorescent groups in the near-infrared region include but are not limited to Cy5, Cy7, and indocyanine green.
  • Another aspect of the present invention provides an application of the above-mentioned polypeptide probe in the preparation of a diagnostic kit for endometriosis.
  • Another aspect of the present invention provides a diagnostic kit for endometriosis, comprising any of the polypeptide probes described above.
  • the identification polypeptide provided by the present invention can be used for the purpose of diagnosis and treatment of endometriosis.
  • the recognition polypeptide provided by the present invention can be used as a targeted modification polypeptide to enhance the targeting and therapeutic properties of drugs and drug carriers.
  • the identification polypeptide provided by the present invention has wide application prospects and low cost because of its short polypeptide size and easy to be synthesized and modified.
  • the multivariate derivative candidate polypeptide provided by the present invention provides a broad selection strategy of diagnostic and therapeutic compounds or drugs for its practical application.
  • the polypeptide molecule provided by the present invention can specifically identify ectopic endometrial lesions, and provides a specific identification tool for the diagnosis and treatment of patients with endometriosis. Due to the conservation and specificity of the sequence, the present invention is suitable for various basic clinical researches and applications of human endometriosis disease, and is also suitable for use as a research tool in endometriosis modeling experimental animals.
  • FIG. 1 is a graph of fluorescence signal detection at a lesion in an embodiment of the present invention.
  • the present invention takes the polypeptide sequence described in SEQ ID No. 1 as an example.
  • polypeptide sequence is industrially synthesized by a specialized polypeptide preparation company.
  • the amino acid at the C-terminal is linked to the N-terminal.
  • the amino acids are linked one by one, and then the crude peptide is precipitated and centrifuged with excess ether.
  • the crude peptide is purified by HPLC, and finally , mass spectrometry analysis, liquid nitrogen quick freeze drying for use.
  • This example provides a polypeptide probe, which uses the polypeptide sequence prepared in Example 1 and combines it with a fluorescent dye through a conventional organic chemical reaction.
  • mice of C57 strain were purchased. After anesthesia, one side of the uterine tissue was taken, and 2 square millimeters of endometrial tissue was excised. The ectopic inoculation was performed on the abdominal mesentery, and then the abdominal wall muscles and skin were sutured. The entire surgical operation was fully sterilized, and the mice were kept for more than one month for use.
  • Example 3 To the endometriosis mouse model prepared in Example 3, after resting for 1-2 months, and after the formation of ectopic lesions, the polypeptide probe prepared in Example 2 was injected into the tail vein, 24 Hours later, the ectopic endometrial tissue was sampled and fixed, frozen sectioned in the dark, and observed under a confocal microscope, and specific fluorescent signals were seen (as shown in Figure 1).
  • identification polypeptide provided by the present application can be used for the purpose of diagnosis and treatment of endometriosis.

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Abstract

一种异位子宫内膜识别多肽及其衍生物和应用，属于医学细胞生物学领域。所述异位子宫内膜识别多肽，包括以下序列中的一条或多条的组合，SEQ ID No.1，SEQ ID No.2，SEQ ID No.3，SEQ ID No.4，SEQ ID No.5，SEQ ID No.6。该类多肽分子可特异识别异位子宫内膜病灶组织，为子宫内膜异位症病患的诊疗提供了一种特异的识别工具。由于序列的保守性和特异性，其适用于人类子宫内膜异位症疾病的各种基础临床研究及应用，也适用于作为子宫内膜异位症造模实验动物中的研究工具。

Description

异位子宫内膜识别多肽及其衍生物和应用 技术领域
本发明属于医学细胞生物学领域，涉及一种异位子宫内膜识别多肽及其衍生物和应用。
背景技术
子宫内膜异位症是指子宫内膜组织中的活性细胞在机体子宫内膜以外的位置附着生长而形成的一种妇科疾病。有研究估计截至2015年全球有一千多万人受到影响。女性中约有6-10％受其影响。最常见发病部位是在卵巢、输卵管、以及子宫与卵巢周围的组织上。主要症状是骨盆疼痛和不育。其发病原因尚不完全清楚。子宫内膜异位症区域会渗血导致炎症和瘢痕形成。诊断通常基于症状并结合医学影像学，活检是最可靠的诊断方法。子宫内膜异位症尚无治愈方法，但许多治疗方法可改善其症状。由于缺乏特异的诊断标志物，子宫内膜异位症通常会被误诊。因此，针对这一疑难杂症，寻找特异的诊断识别物是极具价值的。
发明内容
为了解决上述背景技术中所提出的问题，本发明的目的在于提供一种异位子宫内膜识别多肽及其衍生物和应用。
为了达到上述目的，本发明所采用的技术方案为：
本发明一方面提供了一种异位子宫内膜识别多肽，包括以下序列中的一条或多条的组合，
Figure PCTCN2020103288-appb-000001
进一步地，所述多肽的纯度为50-100％。
更进一步地，所述多肽的纯度为90-95％。
本发明另一方面提供了一种上述任一所述的异位子宫内膜识别多肽的衍生物，所述的衍生物为异位子宫内膜识别多肽进行末端或侧链的修饰得到的产物，或异位子宫内膜识别多肽进行荧光基团的标记修饰得到的产物，或异位子宫内膜识别多肽进行同位素标记得到的产物，或异位子宫内膜识别多肽进行磷酸化修饰得到的产物，或异位子宫内膜识别多肽进行基于二硫键的环化修饰得到的产物，或异位子宫内膜识别多肽进行生物素的标记得到的产物，或异 位子宫内膜识别多肽进行光敏剂修饰得到的产物，或异位子宫内膜识别多肽进行叠氮修饰得到的产物，或异位子宫内膜识别多肽进行PEG修饰得到的产物，或异位子宫内膜识别多肽进行甲基化修饰得到的产物，或异位子宫内膜识别多肽进行荧光淬灭基团修饰得到的产物，或异位子宫内膜识别多肽进行蛋白偶联修饰得到的产物，或异位子宫内膜识别多肽进行小分子化合物修饰得到的产物。
进一步地，所述异位子宫内膜识别多肽进行末端或侧链的修饰包括但不限于N端乙酰化修饰，C端的胺化修饰。
进一步地，所述异位子宫内膜识别多肽进行荧光基团的标记修饰中所用的荧光染料包括但不限于FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7，该修饰以便用于荧光检测目的。
进一步地，所述异位子宫内膜识别多肽进行同位素标记中所用的同位素包括但不限于 13C，该修饰用于追踪目的。
进一步地，所述异位子宫内膜识别多肽进行的磷酸化修饰包括但不限于p-Ser、p-Thr、p-Tyr。
进一步地，所述异位子宫内膜识别多肽进行生物素的标记，用于定位检测目的等。
进一步地，所述异位子宫内膜识别多肽进行光敏剂修饰，以便于制备光敏感制剂。
进一步地，所述异位子宫内膜识别多肽进行叠氮修饰，有利于次级的连接反应。
进一步地，所述异位子宫内膜识别多肽进行PEG修饰，用于药物载体制备。
所述的异位子宫内膜识别多肽可通过一般有机化学实验室条件自主合成，也可以通过常规的商业化试剂公司工业合成，即利用固相法合成多肽，在树脂上不同氨基酸之间缩合反应实现定向氨基酸链的合成。多肽的衍生物则在氨基酸完成连接后，施加所需的修饰基团。
本发明再一方面提供了一种上述任一所述的多肽或者上述任一所述的衍生物在制备诊断和/或治疗子宫内膜异位症的药物中的应用。
本发明再一方面提供了一种诊断和/或治疗子宫内膜异位症的药物组合物，包括上述任一所述的多肽或者上述任一所述的衍生物。所述的异位子宫内膜识别多肽及其衍生物可通过常规有机化学方法结合于诊断和/或治疗载体上发挥特异识别功能基础上的应用价值，得到可用于诊疗的疾病干预工具。
本发明再一方面提供了一种多肽探针，所述多肽探针采用上述任一所述的多肽序列或者上述任一所述的衍生物，将其与荧光染料通过常规的有机化学反应(如EDC方法反应连接)结合制得。
进一步地，所述荧光染料选自具有近红外区荧光基团的染料，优选地，所述具有近红外 区荧光基团的染料包括但不限于Cy5、Cy7、吲哚菁绿。
本发明再一方面提供了一种上述所述的多肽探针在制备子宫内膜异位症诊断试剂盒中的应用。
本发明再一方面提供了一种子宫内膜异位症诊断试剂盒，包括上述任一所述的多肽探针。
本发明的有益效果：
(1)本发明提供的识别多肽，可用于子宫内膜异位症的诊疗目的。
(2)本发明提供的识别多肽，可作为靶向修饰多肽以增强药物及药物载体的靶向性和治疗性。
(3)本发明提供的识别多肽，由于其多肽短小易于合成修饰，因此其应用前景广泛，且成本低廉。
(4)本发明提供的多元的衍生物备选多肽，为其实际的应用提供了广泛的诊断治疗化合物或药物的选择策略。
(5)本发明提供的多肽分子可特异识别异位子宫内膜病灶组织，为子宫内膜异位症病患的诊疗提供了一种特异的识别工具。由于序列的保守性和特异性，本发明适用于人类子宫内膜异位症疾病的各种基础临床研究及应用，也适用于作为子宫内膜异位症造模实验动物中的研究工具。
附图说明
图1为本发明实施例中病灶处荧光信号检测图。
具体实施方式
为了更好地理解本发明的内容，下面结合具体实施方法对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。
本发明以SEQ ID No.1所述多肽序列为例。
实施例1：SEQ ID No.1所述多肽序列的制备
所述多肽序列由专门的多肽制备公司工业合成。
利用固相合成多肽法，从C端的氨基酸向N端进行链接，经过树脂活化、氨基酸链接、洗脱保护、检测步骤，逐个链接氨基酸，然后使用过量乙醚沉淀离心，对粗肽过HPLC纯化，最后，质谱分析，液氮速冷冻干备用。
实施例2：多肽探针的制备
本实施例提供一种多肽探针，采用实施例1制备得到的多肽序列，将其与荧光染料通过 常规的有机化学反应结合。
实施例3：子宫内膜异位症小鼠动物模型制备
购买7-8周的成年C57品系雌鼠，麻醉后，取一侧正位的子宫组织，切取2平方毫米大小含子宫内膜组织，异位接种于腹腔肠系膜部位，然后缝合腹壁肌肉及皮肤，整个手术操作过程充分消毒，将小鼠静养一个月以上备用。
实施例4：异位子宫内膜组织取样切片观察
对实施例3中制备的子宫内膜异位症小鼠模型，静养1-2月后，待其异位病灶形成后，对其进行尾静脉注射实施例2中所制备的多肽探针，24小时后，对异位子宫内膜组织取材固定，避光冰冻切片后，共聚焦显微镜下观察，可见特异的荧光信号(如图1所示)。
综上，本申请提供的识别多肽可用于子宫内膜异位症的诊疗目的。
以上所述仅为本发明的具体实施方式，不是全部的实施方式，本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换，均为本发明的权利要求所涵盖。

Claims (10)

  1. 一种异位子宫内膜识别多肽，其特征在于，包括以下序列中的一条或多条的组合，
    Figure PCTCN2020103288-appb-100001
  2. 根据权利要求1所述的多肽，其特征在于，所述多肽的纯度为50-100％，优选地，所述多肽的纯度为90-95％。
  3. 权利要求1-2任一项所述的异位子宫内膜识别多肽的衍生物，其特征在于，所述的衍生物为异位子宫内膜识别多肽进行末端或侧链的修饰得到的产物，或异位子宫内膜识别多肽进行荧光基团的标记修饰得到的产物，或异位子宫内膜识别多肽进行同位素标记得到的产物，或异位子宫内膜识别多肽进行磷酸化修饰得到的产物，或异位子宫内膜识别多肽进行基于二硫键的环化修饰得到的产物，或异位子宫内膜识别多肽进行生物素的标记得到的产物，或异位子宫内膜识别多肽进行光敏剂修饰得到的产物，或异位子宫内膜识别多肽进行叠氮修饰得到的产物，或异位子宫内膜识别多肽进行PEG修饰得到的产物，或异位子宫内膜识别多肽进行甲基化修饰得到的产物，或异位子宫内膜识别多肽进行荧光淬灭基团修饰得到的产物，或异位子宫内膜识别多肽进行蛋白偶联修饰得到的产物，或异位子宫内膜识别多肽进行小分子化合物修饰得到的产物。
  4. 根据权利要求3所述的衍生物，其特征在于，所述异位子宫内膜识别多肽进行末端或侧链的修饰包括N端乙酰化修饰，C端的胺化修饰；
    优选地，所述异位子宫内膜识别多肽进行荧光基团的标记修饰中所用的荧光染料包括FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7；
    优选地，所述异位子宫内膜识别多肽进行同位素标记中所用的同位素包括 13C；
    优选地，所述异位子宫内膜识别多肽进行的磷酸化修饰包括p-Ser、p-Thr、p-Tyr。
  5. 权利要求1-2任一项所述的多肽或者权利要求3-4任一项所述的衍生物在制备诊断和/或治疗子宫内膜异位症的药物中的应用。
  6. 一种诊断和/或治疗子宫内膜异位症的药物组合物，其特征在于，包括权利要求1-2任一项所述的多肽或者权利要求3-4任一项所述的衍生物。
  7. 一种多肽探针，其特征在于，所述多肽探针采用权利要求1-2任一项所述的多肽或者权利要求3-4任一项所述的衍生物，将其与荧光染料通过常规的有机化学反应结合制得。
  8. 根据权利要求7所述的多肽探针，其特征在于，所述荧光染料选自具有近红外区荧光基团的染料；优选地，所述具有近红外区荧光基团的染料包括Cy5、Cy7、吲哚菁绿。
  9. 权利要求7或8所述的多肽探针在制备子宫内膜异位症诊断试剂盒中的应用。
  10. 一种子宫内膜异位症诊断试剂盒，其特征在于，包括权利要求7或8所述的多肽探针。
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