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
• 负责人: Lubell, William
• 金额: $ 5.76万
• 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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=692046
• 关键词: Advances; Amino; Acid; Chemistry; Peptide

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. **

肽结构分子识别的自然科学研究是一项基本追求，具有对各个领域产生巨大影响的潜力。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。对肽的兴趣在其他领域也有类似的增长，部分原因是在信息存储、催化和材料科学方面的实用性。肽具有柔韧性和可降解性，在食物和生理系统中的内源性信使中发挥短暂作用；然而，对于需要刚性和较长作用持续时间的任务来说，这些特性通常是缺点。深入了解这一困境的核心，我们的肽拟态研究计划的目标是系统地研究结构-活性关系的工具，以深入了解活性构象异构体以及改善其药代动力学特性的方法。***我们的 NSERC 发现资助计划专注于新型有机合成方法来制备密集功能化的分子，以检查电子和结构力对肽几何和识别的影响。 引入了有效的溶液和固相化学来制备三大类肽模拟物：氨基酸电子等排物、杂环肽杂化物和肽大环化合物。我们的基础计划以初步结果的坚实基础为基础，并融入合作应用研究，现在处于理想的位置，可以加速解决当代肽科学紧迫问题的进展。具体来说，将检查可电离侧链、转角构象异构体和螺旋骨架几何形状的重要性，以增强肽细胞渗透性和生物利用度，对抗耐药性并破坏自聚集。 ***所提出的肽模拟靶标的化学合成对培训高素质人员来说是一个巨大的挑战，他们负责开发用于选择性肽修饰的官能团耐受方法，以引入等排残基、安装构象约束和环化序列。 在战略合作中研究肽拟态化学，学生们接受相关培训，成为了解现代合成化学、光谱技术知识的领导者，以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。 ***对拟议的肽模拟靶点的研究对于解决关键的未满足的医疗需求至关重要，以开发治疗微生物感染和淀粉样蛋白疾病的新疗法，从而提高加拿大的生活质量。我们的项目主要专注于基于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，包括高分子科学、催化和天然产物合成。 **