CAREER: Synthesis of Functional Biomolecules from Tunable N-aryl Peptide Precursors

在化学系SYN项目的支持下，北卡罗来纳州立大学（NCSU）的Caroline Proulx博士将从事生物有机化学的基础研究，重点是开发合成肽和蛋白质模拟文库的新方法。肽在调节生物功能中起着至关重要的作用。它们以高亲和力和选择性结合目标的能力取决于它们的化学组成和构象。因此，需要快速修改和控制两者的工具来简化药物发现工作。在这个项目中，开发了新的方法来实现这些目标。选择性化学转化为后期肽功能化开发，并开发了方法，他们随后的环化/连接在温和的水条件下。探索了功能基团的战略性结合，以控制所产生的肽或蛋白质模拟物的构象和稳定性。该项目更广泛的影响将包括在夏季继续指导和培训ACS项目SEED高中学生和NSF REU学生，以及在北卡罗莱纳州的高中进行教育演讲。虚拟实验室之旅和其他视频也将与NCSU的科学馆合作制作。根据该奖项，Caroline Proulx博士将开发新的方法来获取构象受限的，高度功能化的酮肟和酮酮肽，从可调节的n -芳基肽前体开始。这些底物有望在无催化剂的水条件下进行触发连接，同时也表现出高官能团耐受性。该项目旨在利用后期肽功能化反应在结扎部位引入广泛的侧链化学。α -碳取代基将用于更好地模拟天然氨基酸侧链，微调连接的稳定性，并控制所得到的酮酮或酮肟连接肽的E/Z比。此外，n-芳基环将被调整为能够一锅连续连接，以合成蛋白质长度的材料。从长远来看，这项工作旨在为这类新的非自然肽和蛋白质模拟低聚物的化学生物学建立结构-折叠-功能规则奠定基础。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the SYN program in the Division of Chemistry, Dr. Caroline Proulx of North Carolina State University (NCSU) will pursue fundamental research in bioorganic chemistry, with a focus on developing new methods for the synthesis of peptide- and protein-mimicking libraries. Peptides play vital roles in modulating biological function. Their ability to bind to their targets with high affinity and selectivity is dependent on both their chemical composition and conformation. As such, tools to rapidly modify and control both are required to streamline drug discovery efforts. In this project, novel methods are developed to achieve these goals. Selective chemical transformations are developed for late-stage peptide functionalization, and methods are developed for their subsequent cyclization/ligation under mild aqueous conditions. Strategic incorporation of functional groups is explored to control the conformation and stability of the resulting peptide or protein mimics. Broader impacts of the project will include continued mentoring and training of ACS Project SEED high school students and NSF REU students during the summer, as well as educational presentations in high schools across North Carolina. Virtual lab tours and other videos will also be produced in collaboration with the Science House at NCSU. Under this award, Dr. Caroline Proulx will develop new methods to access conformationally-constrained, highly functionalized ketoxime and kethydrazone peptides starting from tunable N-aryl peptide precursors. These substrates are expected to undergo triggered ligations under catalyst-free aqueous conditions that also exhibit high functional group tolerance. This project aims to introduce a wide array of side chain chemistry at the site of ligation using late-stage peptide functionalization reactions. The alpha-carbon substituent will be used to better mimic natural amino acid side chains, fine-tune stability of the linkage, and control E/Z ratios in the resulting kethydrazone or ketoxime-linked peptides. In addition, the N-aryl ring will be tuned to enable one-pot, sequential ligation for the synthesis of protein-length material. In the longer term, this work seeks to lay the groundwork for the establishment of structure-folding-function rules for this new class of unnatural peptide- and protein-mimicking oligomers for chemical biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.