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用于合成肽的催化方法。肽越来越成为有吸引力的治疗候选物，但它们的合成仍然效率低下且原子不经济。 现代肽合成利用固相方法，其中肽链的氨基酸连接以指定的顺序一次一个地添加。当它被引入时，这项技术彻底改变了肽合成，但目前实施的是一个非常浪费的过程，典型的反应条件是使用过量的偶联剂-高达五倍-对于每个合成的酰胺键。 Arora博士的工作旨在建立一种催化方法，从现成的起始材料中构建酰胺键。 在新的方法中，过量偶联剂的使用被在高效的“绿色”催化循环内操作的优化催化剂所取代。 如果成功，这种方法将对肽，蛋白质和聚合物合成技术和制药应用产生重要影响。 本研究将提供有价值的训练，学生在有机化学和化学生物学的接口。参与该项目的学生将获得分子设计，构象分析，有机合成和生物化学方面的广泛经验，并学习设计具有生物医学研究实际应用的化合物。PI将与Spelman学院合作，在该大学建立一个本科生研究课程，培训Spelman的学生进行肽合成，并让学生评估设计和合成的肽作为抗菌剂的潜力。该项目的目标是开发新的酰胺键合成方法，既原子效率又可持续。迫切需要不需要过量试剂并且足够温和以避免与活化羰基相邻的立构中心的差向异构化的方法。 在这个项目中，酰胺键的形成是加速的有机催化剂，瞬时强制执行的羧基和两个片段的胺末端之间的氢键介导的分子内反应。新方法通过非共价和共价相互作用与底物结合，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：在纽约大学和斯佩尔曼学院的本科化学课程，包括有机，无机化学和生物化学，突出了化学分支学科的基本相互联系的基础上，新的实验室实验模块的整合。该项目将支持与斯佩尔曼学院的合作-一个顶级HBCU（历史上的黑人学院/大学），学生渴望从事尖端研究。 阿罗拉教授将开发一门化学生物学课程，该课程不需要大量资源，但通过前沿的研究项目丰富课程，并为学生提供扩展最先进化学技术知识的机会，包括肽化学、分子建模、结构-活性关系、该奖项反映了NSF的法定使命，并被认为是值得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的支持。

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.