CN109485712A - 二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer - Google Patents

二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer Download PDF

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CN109485712A
CN109485712A CN201811402581.6A CN201811402581A CN109485712A CN 109485712 A CN109485712 A CN 109485712A CN 201811402581 A CN201811402581 A CN 201811402581A CN 109485712 A CN109485712 A CN 109485712A
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dimer
rgia
peia
conotoxin
polypeptide
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于日磊
梁家珍
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Ocean University of China
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Ocean University of China
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Pain & Pain Management (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Tropical Medicine & Parasitology (AREA)
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  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

本发明公开了二聚体Vc1.1‑dimer，RgIA‑dimer和PeIA‑dimer，二聚体α‑芋螺毒素Vc1.1，RgIA和PeIA为多肽类化合物，通过设计一个含有两个炔基官能团的linker，并对野生型的多肽进行修饰，引入叠氮官能团，继而通过click反应从而合成Vc1.1‑dimer，RgIA‑dimer和PeIA‑dimer。本发明的有益效果是通过二聚体的方式提高α‑芋螺毒素对α9α10乙酰胆碱受体的活性与选择性，以便开发出新的用于治疗疼痛与肿瘤的多肽药物。

Description

二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer
技术领域
本发明属于医药技术领域，涉及二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer。
背景技术
α9α10乙酰胆碱受体(nAChR)为近年来新发现的乙酰胆碱受体亚型之一，是治疗慢性疼痛的靶标，对外伤和化疗引起的疼痛具有明显作用，另外α9α10在肿瘤细胞中被过量表达，因此可作为抗肿瘤靶标。而芋螺毒素(Conotoxin,CTX)是由生活在热带海洋中的肉食性软体动物芋螺(Conus)分泌出来的，用于麻醉猎物的小肽类毒素，为一些由10-40个氨基酸组成的，富含二硫键的短肽。其中的α-CTX(Vc1.1，RgIA和PeIA等)，能专一性地作用于神经末端的乙酰胆碱受体，起阻断作用，因此，有望开发成为用于治疗神经痛的镇痛药。但是由于人体和老鼠体内α9α10 nAChR的差异性，这些毒素在人体α9α10 nAChR上的活性明显下降，不足以成药。其中Vc1.1本已进入二期临床，结果在人体α9α10 nAChR上活性下降了100倍(相比于老鼠α9α10 nAChR)。因此急需寻找新的方法对α-CTX进行修饰和改造，提高其对人体α9α10乙酰胆碱受体的活性与选择性，从而开发出新的用于治疗神经痛的药物。
发明内容
本发明的目的在于提供二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer，本发明的有益效果是通过二聚体的方式提高α-芋螺毒素对α9α10乙酰胆碱受体的活性与选择性，以便开发出新的用于治疗疼痛或肿瘤的多肽药物。
本发明所采用的技术方案是二聚体α-芋螺毒素Vc1.1，RgIA和PeIA为多肽类化合物，通过设计一个含有两个炔基官能团的linker，并对野生型的多肽进行修饰，引入叠氮官能团，继而通过click反应从而合成Vc1.1-dimer，RgIA-dimer和PeIA-dimer。
进一步，所述Vc1.1-dimer结构式：
所述RgIA-dimer结构式：
所述PeIA-dimer结构式：
附图说明
图1是Vc1.1-dimer分子结构式；
图2是RgIA-dimer分子结构式；
图3是PeIA-dimer分子结构式。
具体实施方式
下面结合具体实施方式对本发明进行详细说明。
二聚体α-芋螺毒素Vc1.1，RgIA和PeIA为多肽类化合物，通过设计一个含有两个炔基官能团的linker，并对野生型的多肽进行修饰，引入叠氮官能团，继而通过click反应从而合成Vc1.1-dimer，RgIA-dimer和PeIA-dimer。
其结构如附图1-3所示(其氨基酸结构均用氨基酸的简写表示)。
实验证明，α9α10乙酰胆碱受体(nAChR)为近年来新发现的乙酰胆碱受体亚型之一，是治疗慢性疼痛的靶标，对外伤和化疗引起的疼痛具有明显作用。α-芋螺毒素Vc1.1，RgIA在老鼠α9α10 nAChR表现出很强活性，但是在人体α9α10 nAChR上实验时，活性却明显下降，分别降低100倍和300倍左右，影响其成药有效性。而采取二聚体的方式，通过linker的方式将两个相同的芋螺毒素连接起来，可以明显提高α-芋螺毒素Vc1.1，RgIA和PeIA对人体α9α10 nAChR的作用力。之前的研究主要是利用click反应合成α-芋螺毒素ImI，以此提高其对同源五聚体α7nAChR的活性和选择性。而本实验旨在于利用此方法合成二聚体Vc1.1，RgIA和PeIA，以此提高其对异源五聚体α9α10 nAChR的活性和选择性。从而为开发出新的用于治疗神经痛与肿瘤的芋螺毒素多肽类药物奠定基础。
以上所述仅是对本发明的较佳实施方式而已，并非对本发明作任何形式上的限制，凡是依据本发明的技术实质对以上实施方式所做的任何简单修改，等同变化与修饰，均属于本发明技术方案的范围内。

Claims (2)

1.二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer，其特征在于：二聚体α-芋螺毒素Vc1.1，RgIA和PeIA为多肽类化合物，通过设计一个含有两个炔基官能团的linker，并对野生型的a多肽进行修饰，引入叠氮官能团，继而通过click反应从而合成Vc1.1-dimer，RgIA-dimer和PeIA-dimer。
2.按照权利要求1所述二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer，其特征在于：所述Vc1.1-dimer结构式：
所述RgIA-dimer结构式：
所述PeIA-dimer结构式：
CN201811402581.6A 2018-11-23 2018-11-23 二聚体Vc1.1-dimer，RgIA-dimer和PeIA-dimer Pending CN109485712A (zh)

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CN110981967A (zh) * 2019-11-22 2020-04-10 中国海洋大学 α-芋螺毒素Mr1.1的二聚体、合成方法及应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110981967A (zh) * 2019-11-22 2020-04-10 中国海洋大学 α-芋螺毒素Mr1.1的二聚体、合成方法及应用
CN110981967B (zh) * 2019-11-22 2022-10-14 中国海洋大学 α-芋螺毒素Mr1.1的二聚体、合成方法及应用

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