Site-Selective Modification of Peptides and Proteins through Noncovalent Interactions

通过非共价相互作用对肽和蛋白质进行位点选择性修饰

• 批准号: 9758198
• 负责人: Christopher Ryan Shugrue
• 金额: $ 6.09万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758198
• 关键词: Achievement; Acids; Address; Antibodies; Binding Sites; Biochemical; Biological; Chemicals; Closure by clamp; Complex; Creativeness; Development; Environment; Goals; Growth; Health; Human; Hydrogen Bonding; Laboratories; Late Effects; Ligands; Location; Matched Group; Mediating; Medicine; Metals; Methods; Modernization; Modification; Peptide Receptor; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Problem Solving; Process; Proteins; Reaction; Reagent; Research; Resistance; Site; Structure; Techniques; Therapeutic; Therapeutic Agents; United States National Institutes of Health; analog; base; catalyst; design; drug candidate; fluorophore; functional group; in vivo; metal complex; new technology; peptide analog; peptide drug; peptide structure; protein aminoacid sequence; pyridine; receptor; small molecule

PROJECT SUMMARY/ABSTRACT This proposed research is centered on the development of new techniques for the site-selective modification of peptide-based drugs. Peptides have emerged as promising, alternative therapeutic agents, yet a number of drawbacks preclude their widespread use. These limitations can be resolved through the late-stage modification of peptide primary sequences, such as through bioconjugation or stapling, yet methods for selectively functionalizing these chemically complex, unprotected peptides is challenging. This proposal focuses on harnessing this functional group richness of peptides for noncovalent interactions between reagents and residues near sites of desired nucleophilic aromatic substitution (SNAr) reactions. First, electrophilic arenes for SNAr will be appended with directing groups to interact with matched sequences on peptides, directing reactivity toward adjacent Cys residues for functionalization Second, Lewis acidic catalysts that are able to further activate arenes for SNAr will be designed to likewise interact with certain peptide residues, enabling the achievement of catalyst- and ligand-control over sites of modification. Both of these strategies will allow for the pairing of particular directing groups or catalysts with specific sequences of residues adjacent to targeted nucleophilic residues, such as Cys. Orthogonal derivatization of peptides containing many reactive residues with a toolbox of reagents, each designed to target a nucleophilic residue in a different environment, could be imagined. This proposal will facilitate the rapid bioconjugation of a variety of relevant molecules to peptide therapeutics to enhance their efficacies, such as small molecule receptors or drugs, fluorophores, other peptides, or even proteins such as antibodies. Multiple functionalizations, such as through stapling, could also be utilized to enhance the peptides’ structural stabilities and their resistance to proteolytic cleavage in vivo. Since few methods for site-selective modification exist, this research would facilitate studies of how alterations to different locations on peptide medicines alter their structure and function, allowing for wider access to more diverse drug analogs. The paradigm of directed reactivity for site-selective peptide modifications would not only be useful for SNAr reactions, but represents a general approach amenable to a multitude of other tagging reagents or metal- mediated processes. These discoveries would serve to accomplish the overarching goal of this project, which is the further development of peptide-based medicines into a powerful, and highly sought-out approach to solve the many challenges to human health today. The Pentelute group at MIT will be an ideal location to conduct this research, given their expertise in peptide synthesis and modification and in the development of peptide therapeutics. Their highly collaborative and team-based laboratory environment will promote exchange of ideas, creativity, and problem solving in tackling the incredibly important topic of modern therapeutics.

项目总结/摘要 这项研究的重点是开发新技术，用于位点选择性修饰 肽类药物肽已经成为有前景的替代治疗剂，但许多肽还没有被发现。 这些缺点妨碍了它们的广泛使用。这些局限性可以通过后期的修改来解决 例如通过生物缀合或钉合，还提供了选择性地 使这些化学上复杂的、未保护的肽官能化是具有挑战性的。该提案的重点是 利用肽的这种官能团丰富性用于试剂之间的非共价相互作用， 所需亲核芳族取代（SNAr）反应位点附近的残基。首先，亲电芳烃用于 SNAr将附加有导向基团以与肽上的匹配序列相互作用，从而导向反应性 第二，刘易斯酸性催化剂，其能够进一步活化 用于SNAr的芳烃将被设计为同样与某些肽残基相互作用，从而能够实现 催化剂和配体控制改性位点。这两种策略都将允许配对 特定的导向基团或催化剂，其具有与靶向亲核基团相邻的特定残基序列， 残基，如Cys。含有多个活性残基的肽的正交衍生化 每种试剂都被设计成在不同的环境中靶向亲核残基。这 该提案将促进各种相关分子与肽治疗剂的快速生物缀合， 增强它们的功效，例如小分子受体或药物、荧光团、其他肽，甚至 蛋白质，如抗体。还可以利用多种官能化，例如通过钉合， 增强肽的结构稳定性和它们对体内蛋白水解切割的抗性。因为很少有方法 对于位点选择性修饰存在，这项研究将有助于研究如何改变不同的位置 肽类药物的研究改变了它们的结构和功能，使人们能够更广泛地获得更多样化的药物类似物。 用于位点选择性肽修饰的定向反应性的范例不仅对SNAr有用， 反应，但代表了适用于多种其他标记试剂或金属的一般方法， 中介过程。这些发现将有助于实现该项目的总体目标，即 肽类药物的进一步发展成为一种强大的，备受欢迎的方法，以解决 当今人类健康面临的诸多挑战。麻省理工学院的Pentelute小组将是进行这一研究的理想地点 研究，鉴于他们在肽合成和修饰以及肽开发方面的专业知识， 治疗学他们高度协作和团队为基础的实验室环境将促进思想交流， 创造力和解决问题的能力，来解决现代治疗学中非常重要的话题。