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库的新方法。肽在调节生物功能中起着重要作用。它们以高亲和力和选择性结合其靶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。选择性的化学转化开发的后期肽功能化，并开发其随后的环化/连接在温和的水性条件下的方法。探索了官能团的策略性掺入以控制所得肽或蛋白质模拟物的构象和稳定性。该项目的更广泛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，以及在北卡罗来纳州的高中进行教育演示。虚拟实验室图尔斯之旅和其他视频也将与NCSU的科学之家合作制作。根据该奖项，Caroline Proulx博士将开发新方法，从可调的N-芳基肽前体开始获得构象受限的高度官能化的酮肟和酮腙肽。预期这些底物在无催化剂的水性条件下进行触发连接，其也表现出高官能团耐受性。该项目旨在使用后期肽功能化反应在连接位点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，并控制所得酮腙或酮亚胺连接的肽中的E/Z比。此外，N-芳基环将被调整以实现一锅法、顺序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天然肽和蛋白质模拟低聚物的化学生物学结构-折叠-功能规则的建立奠定基础。该奖项反映了NSF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.