Peptide Stapling Using Conformationally Constrained Building Blocks

该奖项将资助塔夫茨大学的Joshua Kritzer博士开发新的化学构建块，以控制多肽的形状，以模拟蛋白质中的独特构象。多肽是氨基酸的短聚合链，与较大的蛋白质有许多共同的性质。控制多肽的三维形状或构象的能力允许控制这些性质，从而控制它们的功能。在这个项目中，化学绳索被用来将一种非天然的氨基酸(一种在陆地生物中没有的氨基酸)连接到链上的另一种氨基酸上，以限制多肽的形状。所得多肽在材料科学、催化剂和药物开发等方面具有潜在的应用前景。此外，该项目还通过开发一系列培训工作坊，帮助学生练习专业技能，提供职业指导，促进多样性和包容性，为学生进入科学工作队伍做准备。研究项目采用了一种新的侧链介导的交联剂，或称“订书机”，它利用了非天然氨基酸4-硫代丙氨酸的独特构象特性。使用多种独立的策略将4-巯基-脯氨酸基团结合到多肽中，产生独特种类的订钉的β-发夹、订钉的胶原样螺旋和组件以及订钉的双环肽。通过溶液状态核磁共振波谱确定了所设计的结构支架的三维结构。通过基于细胞的分析来检验新的主链对生物降解和细胞穿透的影响。这项工作的长期和更广泛的科学影响是提供工具和方法来控制多肽结构和生物稳定性，并通过这样做来构建具有特殊用途的多肽，用于化学生物学研究。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Joshua Kritzer of Tufts University to develop new chemical building blocks that control the shape of peptides to mimic distinct conformations seen in proteins. Peptides are short polymer chains of amino acids that share many properties with larger proteins. The ability to control the three-dimensional shape or conformation of peptides allows the control of these properties and, consequently, their functions. In this project, chemical tethers are used to link an unnatural amino acid (one that is not found in terrestrial organisms) to another amino acid along the chain to constrain the shape of the peptide. The resulting peptides have potential applications in materials science, as catalysts and in drug development. In addition, the project prepares students to enter the science workforce through the development of a series of training workshops that help students practice professional skills, provide career guidance, and promote diversity and inclusion.The research project employs a new strategy for side-chain-mediated cross-linking, or “stapling,” that takes advantage of the unique conformational properties of the unnatural amino acid 4-mercaptoproline. Multiple independent strategies are used to incorporate 4-mercaptoproline staples into peptides, producing unique varieties of stapled beta-hairpins, stapled collagen-like helices and assemblies, and stapled bicyclic peptides. The three-dimensional structures of these designed structural scaffolds are determined by solution-state NMR spectroscopy. The effects of the new staples on biological degradation and cell penetration are examined through cell-based assays. The long term broader scientific impact of this work is to provide tools and methodology to control peptide architecture and biological stability and in so doing construct polypeptides with particular utility for studies in 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.