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

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 本申请的目标是为一项文书获得补充资金，该文书对执行 NIGMS资助R35 GM142883的研究目标。受资助的研究试图利用立体化学- 在多肽序列的任何点上，作为生物物理探针来解决当前障碍的钙强健的硫代酰胺 在多肽合成、折叠和药物发现方面。这项建议中的方法是保护硫代酰胺，在 类比保护氨基酸侧链的官能团，以保存硫代酰胺 多肽伸长过程中的部分。这种方法的基本原理是，硫代酰胺保护可以很容易地在- 包括在标准SPPS工作流程中，以实现在多肽合成、主链修饰和 阳离子和蛋白质与药物的相互作用。该项目的研究计划将利用硫代酰胺来探测蛋白质 折叠和选择性插入其他化学物质。硫代酰胺将被用于以前未知的Se- 序列空间来解决蛋白质折叠中的基本问题。我们还将开发方法来转变 将硫代酰胺转化为官能团，将解锁新的受约束的多肽支架。具有持久性的多肽 作为弥合小分子之间性能差距的治疗药物，结构具有巨大的前景 和生物制品。最后，这项工作将确定询问和靶向治疗相关蛋白质的策略- 蛋白质界面。多肽主链氢键供体与受体的相互作用 和蛋白质结合靶点在药物设计中没有得到充分利用。基于结构生物信息学的新战略 确定蛋白质-蛋白质界面(PPI)未被充分利用的相互作用将有助于设计更有效的 抑制剂。其他工作还将开发新的工具来询问PPI，其结构信息非常少 可能会为未来的实验设计提供参考。这项拟议的研究具有创新性，因为它代表了 通过开发和采用新的方法来保护硫代硫酸盐，从而从根本上改变现状 酰胺稳定性，这有望打开新的研究视野。这一贡献意义重大，因为它是 有望在蛋白质折叠的研究和生物活性分子的开发方面具有广泛的重要性。 克洛斯。本应用程序中描述的工具将支持上述所有活动，并且 它们的完成是必要的。