Rational Design of Peptidomimetics Targeting Glucagon-Like Peptide-1 Receptors

针对胰高血糖素样肽 1 受体的肽模拟物的合理设计

基本信息

  • 批准号:
    8002381
  • 负责人:
  • 金额:
    $ 22.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-01-19 至 2011-12-31
  • 项目状态:
    已结题

项目摘要

Protein complex formation through protein-protein or receptor-ligand interaction is a central theme in biological systems and plays critical roles in regulating diverse cellular functions. It is often mediated by α-helical structures and this recognizes short helical peptides as valuable tools to study critical biochemical pathways as well as to ultimately develop therapeutic candidates. However, peptides have serious limitations, such as rapid enzymatic degradation, low bioavailability, and no oral activity, that potentially hamper their effective applications. Thus, non-peptidic α-helix mimetics would be of great interest due to their potentially high enzymatic stability and efficacy. However, α-helix mimetics already reported until now do not represent amphiphilicity, a fundamental feature of most α-helices that significantly contributes to potency and selectivity. Therefore, I have developed a research plan that focuses on development of amphiphilic α-helix mimetics and their applications to emulate α-helical structures found in peptides and proteins. Simultaneous representation of both hydrophobic and hydrophilic surfaces will be important to achieve not only high affinity but also improved selectivity for their target proteins. To demonstrate proof of concepts, we have chosen a peptide hormone, glucagon like peptide-1 (GLP-1) that plays an important physiological role in glucose homeostasis through stimulating insulin secretion and regulating pancreatic β-cell mass and functions, which are highly favorable for treating diabetes. However, its high susceptibility to enzymatic degradation becomes a major obstacle for its effective in vivo applications and highlights the need of potent non-peptide GLP-1 mimetics that have not been achieved yet. Thus, we herein propose a rational approach to design GLP-1 peptidomimetics containing α-helix mimetics that are engineered to represent corresponding α-helical peptide segments in GLP-1. As a seminal observation, one of our recently synthesized prototype α-helix mimetics was found to interact with the GLP-1 receptor and induce receptor stimulation. Furthermore, this compound showed markedly enhanced biological activity when linked to a complementary GLP-1 fragment and led to develop potent GLP-1 peptidomimetics. Encouraged by our initial success, in this research plan we propose (1) to identify important helical faces for receptor interaction by using α-helix mimetics based on the tris-benzamide scaffold; (2) to design and synthesize amphiphilic α-helix mimetics to improve α-helix mimicry for higher potency and selectivity to the GLP-1 receptor; (3) to rationally design and construct GLP-1 peptidomimetics using the α-helix mimetics; (4) to improve biological activity of GLP-1 peptidomimetics through a multivalent architecture; and (5) to characterize and validate α-helix mimicry by structural analysis. The strategies developed in this proposal would be of interest since they can be broadly applied to other medically relevant targets.
通过蛋白质-蛋白质或受体-配体相互作用形成蛋白质复合物是生物学的中心主题 系统,并在调节多种细胞功能中发挥关键作用。它通常由-螺旋介导 结构和这承认短螺旋肽作为有价值的工具,研究关键的生化途径, 并最终开发出治疗候选药物。然而,肽具有严重的局限性,例如, 快速酶降解、低生物利用度和无口服活性,这可能妨碍其有效 应用.因此,非肽-螺旋模拟物由于其潜在的高活性而受到极大的关注。 酶的稳定性和功效。然而,迄今为止已经报道的β-螺旋模拟物并不代表 两亲性是大多数螺旋的基本特征,其显著有助于效力和选择性。 因此,我制定了一个研究计划,重点是开发两亲性螺旋模拟物 以及它们在模拟肽和蛋白质中的螺旋结构方面的应用。同时 疏水和亲水表面的代表性将是重要的, 而且提高了对靶蛋白的选择性。 为了证明概念,我们选择了一种肽激素,胰高血糖素样肽-1 胰高血糖素样肽-1(GLP-1)通过刺激胰岛素分泌在葡萄糖稳态中发挥重要的生理作用 并调节胰腺细胞的质量和功能,这对治疗糖尿病非常有利。 然而,其对酶降解的高度敏感性成为其在体内有效的主要障碍 这一发现表明了GLP-1的应用,并强调了对尚未实现的有效非肽GLP-1模拟物的需求。 因此,我们在此提出了一种合理的方法来设计含有-螺旋的GLP-1肽模拟物 模拟物被工程化以代表GLP-1中相应的β-螺旋肽片段。作为 开创性的观察,我们最近合成的原型之一-螺旋模拟物被发现与 GLP-1受体并诱导受体刺激。此外,该化合物显示出显著增强的 当与互补GLP-1片段连接并导致产生有效GLP-1时, 肽模拟物 在我们初步成功的鼓舞下,在本研究计划中,我们提出(1)确定重要的螺旋 通过使用基于三-苯甲酰胺支架的-螺旋模拟物, 合成两亲性-螺旋模拟物以改善-螺旋模拟,从而获得更高的效力和选择性, GLP-1受体;(3)使用β-螺旋模拟物合理设计和构建GLP-1肽模拟物;(4) 通过多价结构改善GLP-1肽模拟物生物活性;和(5)表征 并通过结构分析来验证-螺旋模仿。本提案中制定的战略将包括: 因为它们可以广泛应用于其他医学相关目标。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Glucagon-like peptide-1 (GLP-1) analogs: recent advances, new possibilities, and therapeutic implications.
  • DOI:
    10.1021/jm500810s
  • 发表时间:
    2015-02-12
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Manandhar B;Ahn JM
  • 通讯作者:
    Ahn JM
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JUNG-MO AHN其他文献

JUNG-MO AHN的其他文献

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{{ truncateString('JUNG-MO AHN', 18)}}的其他基金

Enhancing endoplasmic reticulum stress in ovarian cancer
增强卵巢癌的内质网应激
  • 批准号:
    10453424
  • 财政年份:
    2022
  • 资助金额:
    $ 22.95万
  • 项目类别:
Enhancing endoplasmic reticulum stress in ovarian cancer
增强卵巢癌的内质网应激
  • 批准号:
    10569119
  • 财政年份:
    2022
  • 资助金额:
    $ 22.95万
  • 项目类别:
Development of small molecule epigenetic therapeutics for prostate cancer
前列腺癌小分子表观遗传学疗法的开发
  • 批准号:
    10558443
  • 财政年份:
    2021
  • 资助金额:
    $ 22.95万
  • 项目类别:
Development of small molecule epigenetic therapeutics for prostate cancer
前列腺癌小分子表观遗传学疗法的开发
  • 批准号:
    10254491
  • 财政年份:
    2021
  • 资助金额:
    $ 22.95万
  • 项目类别:

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