Advances in Amino Acid Chemistry and Peptide Mimicry

自然科学对多肽结构的分子识别研究是一项基础性的研究，具有巨大的潜力，将影响到各个领域。例如，预计到2025年，基于多肽的药物在医学上的使用将增长到480.4亿美元的全球市场价值。对多肽的兴趣与其他领域相似，部分原因是在信息存储、催化和材料科学方面的应用。多肽具有弹性和可降解性，在食物和生理系统的内源性信使中起着短暂的作用；然而，对于需要刚性和更长作用时间的任务来说，这种特性往往是缺点。穿透了这一困境的核心，我们在多肽模拟方面的研究计划瞄准了系统研究结构-活性关系的工具，以深入了解活性构象和改善其药代动力学特性的方法。我们的NSERC-Discovery Grant计划专注于新的有机合成方法来制备密集官能化分子，以研究电子和结构力对肽几何和识别的影响，我们的NSERC-Discovery Grant计划引入了有效的溶液和固相化学，用于制作三类主要的肽模拟：氨基酸等位体、杂环-多肽杂化和多肽大环。建立在初步结果的坚实基础上，并整合到协作应用研究中，我们的基础计划现在处于理想的位置，可以加快在多肽科学的紧迫当代问题上的进展。具体地说，将研究可电离侧链、转角构象和螺旋主干几何结构的重要性，以增强多肽细胞的渗透性和生物利用度，对抗耐药性和破坏自我聚集。所提出的多肽模拟靶标的化学合成对于培训高素质的人员来说是一个巨大的挑战，这些人员负责开发用于选择性多肽修饰的官能团容忍方法，以引入等位基残基，安装构象约束，并对序列进行环化。在战略合作中学习多肽模拟的化学，学生们接受有针对性的培训，成为现代合成化学知识的领导者，在光谱技术方面探索分子约束对多肽几何的影响，并与我们的合作者沟通以了解结构-活性关系。对拟议的多肽模拟靶点的研究对于解决加拿大尚未满足的关键医疗需求至关重要，这些需求旨在开发新的疗法来治疗微生物感染和淀粉样蛋白疾病，以提高加拿大的生活质量。我们的计划主要专注于基于多肽的药物化学中的有机合成，受益于广泛的科学兴趣和合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.