Towards a Greener Approach for Chemical Synthesis of Peptides

在化学系化学合成项目的支持下，纽约大学的Paramjit Arora教授将致力于开发一种催化合成多肽的方法。肽越来越成为有吸引力的治疗候选者，但它们的合成仍然效率低下和原子不经济。当代肽合成采用固相方法，其中肽链的氨基酸连接按指定顺序一次添加一个。该技术一经推出就彻底改变了肽合成，但目前实施的过程是一个高度浪费的过程，在典型的反应条件下，每合成一个酰胺键，就需要使用多达五倍的过量偶联剂。阿罗拉博士的工作旨在建立一种从现成的起始材料中构建酰胺键的催化方法。在新的方法中，使用过量的偶联剂被优化的催化剂取代，在一个高效的“绿色”催化循环中运行。如果成功，该方法将对多肽、蛋白质和聚合物合成的技术和制药应用产生重要影响。本研究将在有机化学与化学生物学的交叉领域为学生提供有价值的训练。参与该项目的学生将在分子设计、构象分析、有机合成和生物化学方面获得广泛的经验，并学习设计具有实际应用于生物医学研究的化合物。PI将与Spelman学院合作，在该大学开设本科生研究课程，培训Spelman学院的学生合成多肽，并让学生评估设计和合成的多肽作为抗菌剂的潜力。该项目的目标是开发既具有原子效率又具有可持续性的酰胺键合成新方法。迫切需要一种不需要过量试剂和足够温和的方法来避免靠近活化羰基的立体中心的外显异构化。在这个项目中，通过有机催化剂，在两个片段的羧基端和胺端之间短暂地加强氢键介导的分子内反应，加速了酰胺键的形成。新方法通过非共价和共价相互作用与底物接合，以减少组织催化的最佳过渡态的熵罚。该项目包括重要的教育和推广活动：将基于项目科学的新实验室实验模块整合到纽约大学和斯佩尔曼学院的本科化学课程中，包括有机化学、无机化学和生物化学，突出化学分支学科之间的基本相互联系。该项目将支持与斯佩尔曼学院的合作，斯佩尔曼学院是一所顶尖的HBCU（历史上的黑人学院/大学），学生们渴望从事前沿研究。Arora教授将开设一门化学生物学课程，该课程不需要大量的资源，但通过前沿的研究项目丰富了课程内容，并为学生提供了扩展最新化学技术知识的机会，包括肽化学、分子建模、结构-活性关系和生物正交反应。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 Chemical Synthesis Program in the Division of Chemistry, Professor Paramjit Arora of New York University will work toward the development of a catalytic approach for the synthesis of peptides. Peptides are increasingly becoming attractive therapeutic candidates but their synthesis remains inefficient and atom-uneconomical. Contemporary peptide synthesis utilizes a solid phase approach, where the amino acid links of a peptide chain are added one at a time, in a specified sequence. This technique revolutionized peptide synthesis when it was introduced, but as currently implemented it is a highly wasteful process, with typical reaction conditions utilizing excess equivalents of the coupling agents–up to fivefold–for every amide bond synthesized. Dr. Arora’s work seeks to establish a catalytic approach to the construction of amide bonds from readily available starting materials. In the new approach, the use of excess coupling agents is replaced with optimized catalysts operating within an efficient, “green” catalytic cycle. If successful, this approach will have important implications for peptide, protein, and polymer synthesis for technological and pharmaceutical applications. This research will provide valuable training to students at the interface of organic chemistry and chemical biology. Students engaged in the project will gain broad experience in molecular design, conformational analysis, organic synthesis, and biochemistry, and learn to design compounds with practical applications in biomedical research. In collaboration with Spelman College, the PI will establish an undergraduate research course at that university to train Spelman students in peptide synthesis and allow the students to evaluate the potential of the designed and synthesized peptides as antibacterial agents.The objective of this project is to develop new methods for amide bond synthesis that are both atom-efficient and sustainable. There is an urgent need for methods that do not require excess reagents and are mild enough to avoid epimerization of stereocenters adjacent to the activated carbonyl group. In this project, amide bond formation is accelerated by organocatalysts that transiently enforce a hydrogen-bonding-mediated intramolecular reaction between the carboxyl and amine termini of two fragments. The new approach engages the substrates through non-covalent and covalent interactions to reduce the entropic penalty of organizing the optimal transition state for catalysis. The project includes significant educational and outreach activities: the integration of new laboratory experiment modules based on the science of the project within undergraduate chemistry courses at NYU and Spelman College, including organic, and inorganic chemistry, and biochemistry, highlighting the essential interconnectedness of the chemistry subdisciplines. The project will support a collaboration with Spelman College – a top HBCU (historically Black college/university) with students eager to engage in cutting edge research. Professor Arora will develop a chemical biology course that does not require extensive resources but enriches the curriculum with cutting-edge research-based projects and that provides opportunities for students to expand their knowledge of state-of-the-art chemistry techniques, including peptide chemistry, molecular modeling, structure-activity relationships, and bioorthogonal reactions.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.