Advances in Amino Acid Chemistry and Peptide Mimicry

氨基酸化学和肽模拟的进展

基本信息

  • 批准号:
    RGPIN-2014-06647
  • 负责人:
  • 金额:
    $ 6.12万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2018
  • 资助国家:
    加拿大
  • 起止时间:
    2018-01-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

Peptides are natural biopolymers composed of chains of amino acids. Prominent examples serving as drugs include oxytocin, insulin, cyclosporin and salmon calcitonin, which are widely used in childbirth, diabetes, immunosuppression and osteoporosis, respectively. Research on the synthesis and science of peptides has experienced intense growth in both academic and industrial sectors, because of their remarkable versatility as building blocks and as tools for innovation in various fields. For example, the global market for peptide drugs is predicted to grow at an accelerated rate from US $14.1 billion in 2011 to US $25.4 billion in 2018, with currently, 60-70 approved peptide drugs, 100-200 more in clinical trials, and 400-600 more in pre-clinical studies. Paralleling interest in peptides for medical uses has been proportional growth in research featuring peptides in catalysis, materials science and nano-technology.*Inherent in all peptide research are desires for insight into their active conformers and means to improve their stability and bioavailability. Although peptides evolved to be flexible and degradable for roles such as food and endogenous messengers in physiological systems, such properties are often drawbacks for programs desiring to harness them for specific tasks requiring longer durations of action. Our research program in peptide mimicry penetrates the heart of this predicament by providing tools for systematically studying structure-activity relationships to obtain insight about active conformers and means to improve their specificity and stability. Three classes of peptide mimic will be pursued: turns, loops and amino acid isosteres. Peptide turns are used in nature for various recognition events: e.g., peptide hormone - receptor, peptide antigen - antibody, and between the sites on protein surfaces and the enzymes, which can modify them by adding sugars or phosphates. Mimicry of turns has thus important impact in understanding natural conformations responsible for biological activity and to develop more drug-like molecules from peptide lead structures. Loops are involved in recognition events, which typically demand larger surface areas than turns: e.g., protein recognition by antibodies. We propose a lynchpin strategy to constrain peptide loops, which may be assembled later onto molecular scaffolds in order to mimic proteins that recognize discontinuous surface areas of larger molecules. Isosteres of amino acids are surrogates of these building blocks of peptides and proteins, which may constrain the backbone of these polymers as well as serve as mimics of the state of transition when peptide bonds are hydrolyzed by digestive enzymes and thereby inhibit the latter. All three of these targets have utility for preparing analogs of biologically active peptides to study and replicate the elements responsible for function. Employing these three motifs to study novel peptide targets with four different collaborators, our fundamental studies will be applied to make prototypes of drugs for treating AIDS, cancer and cardiovascular diseases, major causes of death in Canada. Studying the chemistry of these three motifs in such collaborations, my students are well trained in modern synthetic methods, spectroscopic techniques to explore the impact of constraint on peptide geometry and in communication with our biological counterpart to understand relationships between structure and activity. Finally, although focused primarily on using peptides in medicinal chemistry, my program benefits from broad scientific interests and aptitude for collaborative research to capitalize on opportunity impacting other fields: e.g., polymer science, photochromic devices and natural product synthesis.
多肽是由氨基酸链组成的天然生物聚合物。作为药物的突出例子包括催产素、胰岛素、环孢素和鲑鱼降钙素,它们分别广泛用于分娩、糖尿病、免疫抑制和骨质疏松症。多肽的合成和科学研究在学术和工业领域都经历了强劲的增长,因为它们作为构建材料和作为各个领域创新的工具具有非凡的多功能性。例如,预计全球多肽药物市场将从2011年的141亿美元加速增长到2018年的254亿美元,目前批准的多肽药物有60-70种,还有100-200种在临床试验中,还有400-600种在临床前研究中。人们对用于医疗用途的多肽感兴趣的同时,以催化、材料科学和纳米技术中的多肽为特色的研究也成比例增长。*所有多肽研究的本质都是对其活性构象的洞察以及提高其稳定性和生物利用度的手段的渴望。尽管对于生理系统中的食物和内源性信使等角色,多肽进化成了灵活和可降解的角色,但对于希望利用它们来执行需要更长持续时间的特定任务的程序来说,这样的特性往往是缺点。我们在多肽模拟方面的研究计划通过提供工具系统地研究结构-活性关系来深入了解活性构象,以及提高它们的特异性和稳定性的方法,深入了解了这一困境的核心。我们将研究三类多肽模拟物:转体、环状和氨基酸等位体。在自然界中,多肽转折被用于各种识别事件:例如,多肽激素受体、多肽抗原抗体,以及蛋白质表面和酶之间的识别事件,这些酶可以通过添加糖或磷酸盐来修饰它们。因此,转角的模拟对于理解与生物活性有关的自然构象以及从肽的先导结构中开发更多的类药物分子具有重要的影响。环路涉及识别事件,这通常需要比转弯更大的表面积:例如,抗体识别蛋白质。我们提出了一种关键的策略来限制多肽环,这些多肽环可能稍后被组装到分子支架上,以便模仿识别大分子不连续表面区域的蛋白质。氨基酸的同位异构体是这些构成多肽和蛋白质的积木的替代品,它们可以限制这些聚合物的主干,也可以模拟消化酶对多肽键进行水解时的过渡状态,从而抑制后者。所有这三个靶点都可用于制备生物活性多肽的类似物,以研究和复制负责功能的元件。利用这三个基序与四个不同的合作者研究新的多肽靶点,我们的基础研究将应用于制造治疗艾滋病、癌症和心血管疾病的药物原型,这些疾病是加拿大的主要死亡原因。在这样的合作中学习这三个基序的化学,我的学生在现代合成方法、光谱技术方面都得到了很好的培训,以探索限制对肽几何的影响,并与我们的生物同行沟通,以了解结构和活性之间的关系。最后,虽然我的项目主要集中在药物化学中使用多肽,但我的项目受益于广泛的科学兴趣和合作研究的天赋,以利用影响其他领域的机会:例如,聚合物科学、光致变色设备和天然产品合成。

项目成果

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Lubell, William其他文献

Lubell, William的其他文献

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{{ truncateString('Lubell, William', 18)}}的其他基金

Advances in Amino Acid Chemistry and Peptide Mimicry
氨基酸化学和肽模拟的进展
  • 批准号:
    RGPIN-2019-04079
  • 财政年份:
    2022
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Discovery Grants Program - Individual
Advances in Amino Acid Chemistry and Peptide Mimicry
氨基酸化学和肽模拟的进展
  • 批准号:
    RGPIN-2019-04079
  • 财政年份:
    2021
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Discovery Grants Program - Individual
Advances in Amino Acid Chemistry and Peptide Mimicry
氨基酸化学和肽模拟的进展
  • 批准号:
    RGPIN-2019-04079
  • 财政年份:
    2020
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Discovery Grants Program - Individual
Azacyclopeptide Modulators of Immuno-metabolism to Treat Age-Related Macular Degeneration
氮杂环肽免疫代谢调节剂治疗年龄相关性黄斑变性
  • 批准号:
    538816-2019
  • 财政年份:
    2020
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Collaborative Health Research Projects
Advances in Amino Acid Chemistry and Peptide Mimicry
氨基酸化学和肽模拟的进展
  • 批准号:
    RGPIN-2019-04079
  • 财政年份:
    2019
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Discovery Grants Program - Individual
Azacyclopeptide Modulators of Immuno-metabolism to Treat Age-Related Macular Degeneration
氮杂环肽免疫代谢调节剂治疗年龄相关性黄斑变性
  • 批准号:
    538816-2019
  • 财政年份:
    2019
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Collaborative Health Research Projects
Urgent Replacement of 700 MHz NMR CryoPlatform
紧急更换 700 MHz NMR CryoPlatform
  • 批准号:
    RTI-2020-00673
  • 财政年份:
    2019
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Research Tools and Instruments
Liquid chromatography-mass spectrometry (LCMS) instrument
液相色谱-质谱(LCMS)仪器
  • 批准号:
    RTI-2019-00136
  • 财政年份:
    2018
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Research Tools and Instruments
Targeting the interleukin-1 receptor for treating ischemic eye diseases
靶向白介素 1 受体治疗缺血性眼病
  • 批准号:
    493638-2016
  • 财政年份:
    2017
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Collaborative Health Research Projects
Advances in Amino Acid Chemistry and Peptide Mimicry
氨基酸化学和肽模拟的进展
  • 批准号:
    RGPIN-2014-06647
  • 财政年份:
    2017
  • 资助金额:
    $ 6.12万
  • 项目类别:
    Discovery Grants Program - Individual

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Amplification of chiral recognition and discrimination among amino-acid-based nanoscale ions during assembly induced by electrostatic interaction
静电相互作用诱导组装过程中氨基酸纳米级离子之间手性识别和辨别的放大
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  • 批准号:
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