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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=737393
• 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具有显著潜力的基础研究，将对各个领域产生重大影响。例如，到2025年，肽类药物在医学上的使用预计将增长到480.4亿美元的全球市场价值。由于在信息存储、催化和材料科学方面的应用，人们对多肽的兴趣也在其他领域得到了类似的增长。多肽具有灵活性和可降解性，在食物和生理系统中的内源性信使中起着短暂的作用；然而，对于要求刚性和动作持续时间较长的任务，这种特性往往是缺点。深入到这一困境的核心，我们的研究计划在肽模拟目标工具系统地研究结构-活性关系，以获得有关活性构象的见解和手段，以改善其药代动力学性质。我们的nserc发现资助项目专注于新的有机合成方法，以制备密集功能化分子，以研究电子和结构力对肽几何形状和识别的影响，我们引入了有效的溶液和固相化学方法来制造三大类肽模拟物：氨基酸同异构体、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，我们的基础项目现在理想地定位于加速肽科学中紧迫的当代问题的进展。具体来说，可电离侧链、旋转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，以对抗耐药性和破坏自聚集。所提出的肽模拟靶点的化学合成对培养高素质人才来说是一项艰巨的挑战，他们负责开发功能基耐受性方法，用于选择性肽修饰，引入等压残基，安装构象约束，并对序列进行环化。在战略合作中研究肽模拟的化学，学生将接受相关的培训，成为现代合成化学的领导者，在光谱技术方面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。研究拟议的肽模拟靶点对于解决关键的未满足的医疗需求，开发新的治疗方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至关重要。我们的项目主要专注于以肽为基础的药物化学的有机合成，受益于广泛的科学兴趣和协作自然科学研究的能力，以抓住对各个领域有影响的发现，包括聚合物科学，催化和天然产物合成。