Advances in Amino Acid Chemistry and Peptide Mimicry

肽结构的分子识别的自然科学研究是一个基本的追求，具有显着的潜力，影响到各个领域。例如，到2025年，基于肽的药物在医学中的使用预计将增长到480.4亿美元的全球市场价值。对肽的兴趣的类似增长被其他领域所取代，部分原因是信息存储，催化和材料科学的实用性。柔性和可降解的肽在食物中和生理系统中的内源性信使中起短暂作用;然而，这些特性通常是需要刚性和较长作用持续时间的任务的缺点。穿透这一困境的核心，我们在肽模拟的研究计划的目标工具，系统地研究结构-活性关系，以获得有关活性构象和手段，以改善其药代动力学特性的见解。专注于新的有机合成方法，以制备密集功能化的分子，用于研究电子和结构力对肽几何形状和识别的影响，我们的NSERC发现资助计划引入了有效的溶液和固相化学，用于制造三种主要的肽模拟物：氨基酸电子等排体，杂环肽杂合体和肽大环。建立在初步结果的坚实基础上，并整合在合作应用研究中，我们的基础计划现在处于理想的位置，以加速肽科学中紧迫的当代问题的进展。具体而言，电离侧链，转动构象和螺旋骨架几何形状的重要性将被检查，以提高肽细胞的渗透性和生物利用度，以打击耐药性和破坏自聚集。* 所提出的肽模拟靶标的化学合成体现了对培养高素质人员的巨大挑战，这些人员负责开发用于选择性肽修饰的官能团耐受方法，以引入电子等排残基，安装构象约束，并环化序列。 在战略合作中研究肽模拟的化学，学生接受相关的培训，成为现代合成化学知识渊博的领导者，在光谱技术中探索分子约束对肽几何形状的影响，并与我们的合作者沟通，以了解结构-活性关系。* 对拟议的肽模拟物靶标的研究对于解决开发治疗微生物感染和淀粉样蛋白疾病的新疗法以改善加拿大生活质量的关键未满足的医疗需求至关重要。主要集中在基于肽的药物化学中的有机合成，我们的计划受益于广泛的科学兴趣和协作自然科学研究的能力，以抓住对各个领域产生影响的发现，包括聚合物科学，催化和天然产物合成。 **

Natural Science research on the molecular recognition of peptide structures is a fundamental pursuit with remarkable potential to impact on various fields. For example, the use of peptide-based drugs in medicine is predicted to grow to a global market value of US $48.04 billion by 2025. Similar growth in interest in peptides is paralleled by other fields due in part to utility in information storage, catalysis and materials science. Flexible and degradable, peptides serve transient roles in food and endogenous messengers in physiological systems; however, such properties are often drawbacks for tasks requiring rigidity and longer duration of action. Penetrating the heart of this predicament, our research program in peptide mimicry targets tools for systematically studying structure-activity relationships to obtain insight about active conformers and means to improve their pharmacokinetic properties.***Focused on novel organic-synthesis methods to prepare densely functionalized molecules for examining influences of electronic and structural forces on peptide geometry and recognition, our NSERC-Discovery Grant program has introduced effective solution- and solid-phase chemistry for making three major classes of peptide mimic: amino acid isosteres, heterocycle-peptide hybrids, and peptide macrocycles. Building on a solid foundation of preliminary results and integrated in collaborative applied research, our fundamental program is now ideally positioned to accelerate advances on pressing contemporary issues in peptide science. Specifically, the importance of ionizable side chains, turn conformers and helical backbone geometry will be examined to enhance peptide cell permeability and bioavailability, to combat drug-resistance and to disrupt self-aggregation. ***Chemical synthesis of the proposed peptide mimic targets embodies a formidable challenge for training highly qualified personnel, who are charged to develop functional-group tolerant methods for selective peptide modification to introduce isosteric residues, to install conformational constraint, and to cyclize the sequence. Studying the chemistry of peptide mimicry in strategic collaborations, students receive pertinent training to become leaders knowledgeable in modern synthetic chemistry, in spectroscopic techniques to explore the impact of molecular constraint on peptide geometry, and in communication with our collaborators to understand structure-activity relationships. ***Study of the proposed peptide mimic targets is paramount for tackling critical unmet medical needs for developing new therapy to treat microbial infection and amyloid diseases for improved quality of life in Canada. Focused primarily on organic synthesis in peptide-based medicinal chemistry, our program benefits from broad scientific interests and aptitude for collaborative natural science research to seize upon discoveries with impact on various fields, including polymer science, catalysis and natural product synthesis. **