Advances in Amino Acid Chemistry and Peptide Mimicry

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。肽的合成和科学研究在学术和工业部门都经历了激烈的增长，因为它们在各个领域作为构建模块和创新工具的显着多功能性。例如，全球多肽药物市场预计将从2011年的141亿美元加速增长到2018年的254亿美元，目前有60-70种已获批准的多肽药物，100-200种处于临床试验阶段，400-600种处于临床前研究阶段。在多肽用于医疗用途的同时，在催化、材料科学和纳米技术方面的研究也呈比例增长。所有肽研究中固有的愿望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。虽然多肽在生理系统中具有灵活性和可降解性，如食物和内源性信使，但对于希望利用它们完成需要较长时间作用的特定任务的计划来说，这种特性往往是缺点。我们在肽模拟方面的研究项目通过提供系统研究结构-活性关系的工具来深入了解活性构象，并提高其特异性和稳定性，从而深入了解这一困境的核心。三种类型的肽模拟将被追求：转，环和氨基酸同位体。肽转化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，以及蛋白质表面和酶之间的位点，可以通过添加糖或磷酸盐来修饰它们。因此，旋转的模仿对于理解负责生物活性的自然构象以及从肽导联结构中开发更多类似药物的分子具有重要影响。环路参与识别事件，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策略来约束肽环，这些肽环可能稍后组装到分子支架上，以模拟识别大分子不连续表面积的蛋白质。氨基酸同位异构体是这些多肽和蛋白质的替代物，它可以约束这些聚合物的骨架，并在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。这三种靶标均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，这些是加拿大的主要死亡原因。在这样的合作中研究这三种基序的化学性质，我的学生在现代合成方法、光谱技术方面训练有素，可以探索约束对肽几何形状的影响，并与我们的生物对应物交流，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，但我的项目受益于广泛的科学兴趣和合作研究的才能，以利用影响其他领域的机会：例如聚合物科学，光致变色装置和天然产物合成。

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.