Development of Thioester Exchange for Generation and Screening of Cyclic Peptides for Nucleic Acid Recognition

化学部生命过程化学(CLP)项目的这一奖项支持北卡罗来纳大学教堂山分校的Marcey Waters教授开展基础研究，开发一种高通量方法来合成和鉴定具有生物功能的环肽。环肽是一类与蛋白质和核酸结合的“特权”分子，因为它们具有抗蛋白酶和良好的模拟蛋白质结构域的能力。然而，对于环肽文库的合成和筛选，目前还没有很好的方法。这项建议中描述的方法通过开发一种称为动态组合化学的平衡筛选方法来解决目前的局限性。这里提出的方法学的一个关键方面是它提供了快速进行环肽的迭代重新设计的方法，不仅是为了优化结合，而且是为了进行结构功能研究和了解结合的关键特征。这项基础研究为这类化合物的应用提供了重大进展，这类化合物介于典型的小分子药物(分子量500)和生物制药之间。该提议的广泛影响从制药行业的潜在应用(即药物发现)到培养高中、本科生和研究生在各种研究领域，包括肽合成和分子生物学。

This award in the Chemistry of Life Processes (CLP) program within the Division of Chemistry supports work by Professor Marcey Waters at UNC Chapel Hill to carry out fundamental studies on development of a high-throughput method for the synthesis and identification of cyclic peptides with biological function. Cyclic peptides are a "privileged" class of molecules for binding to proteins and nucleic acids due to their protease-resistance and excellent ability to mimic protein domains. However, there are few good methods for the synthesis and screening of libraries of cyclic peptides. The methodology described in this proposal provides a solution to current limitations through development of an equilibrium screening approach called dynamic combinatorial chemistry. A key aspect of the methodology proposed here is that it offers rapid approach to perform iterative re-design of cyclic peptides, not only to optimize binding, but to perform structure-function studies and to learn about the critical features for binding. This basic research provides a significant advancement for the application of this class of compounds, which fall in class between typical small molecule drugs (molecular weight 500) and biopharmaceuticals.The broader impacts of the proposal range from potential applications in the pharmaceutical industry (i.e., drug discovery) to the training of high school, undergraduate, and graduate students in a variety of research fields, including peptide synthesis and molecular biology.