Peptide backbone modifications to enhance and study protein folding and binding

肽骨架修饰以增强和研究蛋白质折叠和结合

• 批准号: 10582205
• 负责人: Brett VanVeller
• 金额: $ 7.49万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582205
• 关键词: Address; Amides; Amino Acids; Basic Science; Binding Proteins; Bioinformatics; Biological Products; Biophysics; Chemistry; Development; Diagnosis; Drug Design; Drug Interactions; Experimental Designs; Funding; Future; Grant; Hydrogen Bonding; Methods; Mission; Modification; National Institute of General Medical Sciences; Peptide Synthesis; Peptides; Performance; Prevention; Proteins; Public Health; Research; Research Support; Side; Site; Structure; Therapeutic; Therapeutic Intervention; Thioamides; United States National Institutes of Health; Vertebral column; Work; base; design; drug discovery; functional group; human disease; inhibitor; innovation; instrument; instrumentation; knowledge base; novel; preservation; programs; protein aminoacid sequence; protein folding; protein function; scaffold; small molecule; stable plasma protein solution; targeted treatment; tool; Address; Amides; Amino Acids; Basic Science; Binding Proteins; Bioinformatics; Biological Products; Biophysics; Chemistry; Development; Diagnosis; Drug Design; Drug Interactions; Experimental Designs; Funding; Future; Grant; Hydrogen Bonding; Methods; Mission; Modification; National Institute of General Medical Sciences; Peptide Synthesis; Peptides; Performance; Prevention; Proteins; Public Health; Research; Research Support; Side; Site; Structure; Therapeutic; Therapeutic Intervention; Thioamides; United States National Institutes of Health; Vertebral column; Work; base; design; drug discovery; functional group; human disease; inhibitor; innovation; instrument; instrumentation; knowledge base; novel; preservation; programs; protein aminoacid sequence; protein folding; protein function; scaffold; small molecule; stable plasma protein solution; targeted treatment; tool

PROJECT SUMMARY/ABSTRACT The objective in this application is to obtain supplemental funding for an instrument that is vital to carry out the research objectives of NIGMS grant R35 GM142883. The supported research seeks to exploit stereochemi- cally robust thioamides, at any point in the peptide sequence, as biophysical probes to address current barriers in peptide synthesis, folding, and drug discovery. The approach in this proposal is to protect the thioamide, in analogy to the protection of the functional groups of amino acid side chains, in order to preserve the thioamide moiety during peptide elongation. The rationale for this approach is that thioamide protection can be easily in- cluded within the standard SPPS work-flow to enable novel applications in peptide synthesis, backbone modifi- cation, and protein-drug interactions. The research plans of this project will exploit thioamides to probe protein folding and site-selective insertion other chemistries. Thioamides will be employed in previously uncharted se- quence space to address fundamental questions in protein folding. We will also develop methods to transform thioamides into functional groups that will unlock new constrained peptide scaffolds. Peptides with persistent structure hold tremendous promise as therapeutics to bridge the performance gap between small molecules and biologics. Finally, this work will identify strategies to interrogate and target therapeutically relevant protein- protein interfaces. Interactions between hydrogen bond donors and acceptors of the main-chain of a peptide and a protein binding target are underutilized in drug design. Based on structural bioinformatics, new strategies to identify underutilized interactions at protein-protein interfaces (PPIs) will assist in the design of more potent inhibitors. Other work will also develop new tools to interrogate PPIs for which very little structural information may be available to inform future experimental design. The proposed research is innovative because it repre- sents a substantive departure from the status quo by developing and employing new methods to preserve thio- amide stability, which promises to unlock new research horizons. The contribution is significant because it is expected to have broad importance in both the study of protein folding and the development of bioactive mole- cules. The instrumentation described in this application will support all of the activities outlined above and is necessary for their completion.

项目摘要/摘要 本申请中的目的是获得对仪器的补充资金，这对于执行 NIGMS的研究目标授予R35 GM142883。支持的研究旨在利用立体化学 在肽序列中的任何一点上，Cally稳健的硫酰胺作为生物物理探针以解决当前障碍 在肽合成，折叠和药物发现中。该提议中的方法是保护硫酰胺 类似于保护氨基酸侧链的官能团，以保留硫酰胺 肽伸长过程中的部分。这种方法的理由是，硫酰胺的保护很容易被内置 在标准spps工作流中浮出水面，以实现肽合成中的新应用，主链修饰 阳离子和蛋白质 - 药物相互作用。该项目的研究计划将利用硫酰胺探测蛋白质 折叠和现场选择性插入其他化学。硫酰胺将用于以前未知的SE- 解决蛋白质折叠中基本问题的问题。我们还将开发转换的方法 硫酰胺分为功能组，可以解锁新的约束肽支架。持续的肽 结构具有巨大的希望，因为治疗学可以弥合小分子之间的性能差距 和生物制剂。最后，这项工作将确定质疑和靶向治疗相关蛋白质的策略 - 蛋白质界面。氢键供体和肽主链受体之间的相互作用 蛋白质结合靶标在药物设计中不足。基于结构生物信息学，新策略 在蛋白质蛋白界面（PPI）上确定未充分利用的相互作用将有助于设计更有效 抑制剂。其他工作还将开发新工具来询问PPI，几乎没有结构信息 可能可用于告知未来的实验设计。拟议的研究具有创新性，因为它代表了 通过开发和采用新方法来保存硫酸 - 酰胺稳定性，有望解锁新的研究视野。贡献很重要，因为它是 预计在蛋白质折叠的研究和生物活性摩尔的发展中都具有广泛的重要性 Cules。本应用程序中描述的仪器将支持上述所有活动，并且是 他们完成所必需的。