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
• 负责人: Lubell, William
• 金额: $ 6.12万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=632806
• 关键词: Advances; Amino; Acid; Chemistry; Peptide

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.

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、环孢菌素和鲑鱼降钙素，它们分别广泛用于分娩、糖尿病、免疫抑制和骨质疏松症。肽的合成和科学的研究在学术和工业部门都经历了激烈的增长，因为它们作为构建模块和各个领域的创新工具具有显着的多功能性。例如，全球肽类药物市场预计将加速增长，从2011年的141亿美元增长到2018年的254亿美元，目前有60-70种肽类药物获批，100-200种处于临床试验阶段，400-600种处于临床前研究阶段。肽在催化、材料科学和纳米技术方面的研究成比例地增长，对肽的医学用途产生了极大的兴趣。所有肽研究的内在需求是深入了解其活性构象和提高其稳定性和生物利用度的方法。虽然肽进化为柔性的和可降解的角色，如食物和内源性信使在生理系统中，这样的属性往往是程序的缺点，希望利用它们的特定任务，需要更长的持续时间的行动。我们在肽模拟的研究计划穿透这一困境的心脏，通过提供系统地研究结构-活性关系的工具，以获得有关活性构象和手段，以提高其特异性和稳定性的洞察力。将研究三类肽模拟物：转角、环和氨基酸等排体。肽转角在自然界中用于各种识别事件：例如，肽激素-受体，肽抗原-抗体，以及蛋白质表面上的位点与酶之间，酶可以通过添加糖或磷酸盐来修饰它们。因此，对转角的模仿对于理解负责生物活性的天然构象以及从肽先导结构开发更多药物样分子具有重要影响。环涉及识别事件，其通常需要比转弯更大的表面积：例如，抗体对蛋白质的识别我们提出了一个关键的策略，以限制肽环，这可能会被组装到分子支架上，以模仿蛋白质，识别较大分子的不连续表面区域。氨基酸的电子等排体是肽和蛋白质的这些结构单元的替代物，其可以限制这些聚合物的主链，并且当肽键被消化酶水解时充当过渡状态的模拟物，从而抑制后者。所有这三种靶标都可用于制备生物活性肽的类似物，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。在这样的合作中研究这三个基序的化学，我的学生在现代合成方法，光谱技术方面受过良好的训练，以探索限制对肽几何形状的影响，并与我们的生物学对应物进行交流，以了解结构和活性之间的关系。最后，虽然主要集中在药物化学中使用肽，但我的计划受益于广泛的科学兴趣和合作研究的能力，以利用影响其他领域的机会：例如，聚合物科学、光致变色器件和天然产物合成。