Backbone N-Heteroatom Protein Orthotics

主干 N-杂原子蛋白质矫形器

• 批准号: 2109008
• 负责人: Juan Del Valle
• 金额: $ 46万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2109008&HistoricalAwards=false
• 关键词: Backbone; Heteroatom; Protein; Orthotics

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Juan Del Valle at the University of Notre Dame to investigate a new strategy to stabilize proteins, the workhorses of the cell. Proteins consist of strings of amino acids that fold into specific shapes that are important for biological function. This new design strategy will replace individual atoms along the backbone that hold these amino acids together, allowing the design of protein variants that are resistant to unfolding and degradation. These stabilized protein variants have the potential to be employed in wide-ranging applications in the development of biomaterials and hybrid molecules that can survive physiological conditions and potentially pass through biological membranes. In addition, these engineered biomolecules may be used to catalyze challenging chemical reactions in ways that are similar to those found in natural enzymes. As a result, a chemical toolkit will be created for stabilizing an array of folded shapes that are typically found in the three-dimensional structures of proteins. The fundamental scientific knowledge resulting from these studies will have important implications for human diseases that are affected by unstable or misfolded proteins. This project will provide graduate and undergraduate students, including those from underrepresented minority groups, with rigorous training in laboratory research and scientific communication through presentations at meeting and conferences. In addition, local high school students will receive research experience through the “Molecular Inventors” two-week summer internship program. This research project will integrate biomolecular design, chemical synthesis, conformational analysis, and functional assays to fully characterize the structure, stability, and activity of N-heteroatom-substituted miniature proteins. The Del Valle laboratory recently established methodologies to prepare C(alpha)-substituted N-amino, N-alkoxy, and N-hydroxy peptides through conventional solid-phase peptide synthesis. This project will involve the synthesis of multi-domain proteins featuring amide-to-hydrazide and amide-to-hydroxamate bond replacements. Several biophysical methods will be used to determine the impact of these backbone substitutions on thermal stability. The effects of hydrazino acid and N-hydroxy amino acid incorporation will be examined in the context of alpha-helix, beta-sheet, and polyproline II helix domains. Data gleaned from these studies will then be used to design a hybrid mini-protein and examine whether this approach leads to enhanced catalytic activity. This project is expected to provide new insight into the design of stable proteins that can engage in important biomolecular interactions and exhibit native-like enzymatic function.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.

有了这个奖项，化学司的化学过程计划的化学过程是为巴黎圣母院的胡安·德尔·瓦尔（Juan del Valle）提供资金，以调查稳定蛋白质的新战略，以稳定细胞的工作马。蛋白质由氨基酸的细胞组成，这些氨基酸将其折叠成对生物功能很重要的特定形状。这种新的设计策略将沿骨干沿骨架固定在一起的骨干替代单个原子，从而允许设计具有抗性和降解能力的蛋白质变体。这些稳定的蛋白质变体有可能在生物材料和杂化分子的开发中用于广泛的应用中，这些分子可以生存生物条件并可能通过生物学机制。此外，这些工程生物分子可用于以与天然酶相似的方式催化挑战化学反应。结果，将创建一个化学工具包，以稳定通常在蛋白质的三维结构中发现的一系列折叠形状。这些研究产生的基本科学知识将对受不稳定或错误折叠蛋白影响的人类疾病具有重要意义。该项目将通过会议和会议上的演讲为研究生和本科生，包括来自代表性不足的少数群体不足的少数群体和科学沟通的严格培训。此外，当地高中生将通过“分子发明者”为期两周的暑期实习计划获得研究经验。该研究项目将整合生物分子设计，化学合成，构象分析和功能测定，以充分表征N-异摩鼠 - 取代微型蛋白的结构，稳定性和活性。 Del Valle实验室最近建立了通过常规的固相肽合成来制备C（Alpha）取代的N-氨基，N-烷氧基和N-羟基肽的方法。该项目将涉及多域蛋白质的合成，这些蛋白质具有酰胺至氢氮杂和酰胺到羟氨基键的替代品。将使用几种生物物理方法来确定这些骨干取代对热稳定性的影响。氢锌酸和N-羟基氨基酸的掺入的影响将在α-螺旋，β-片和多生素II螺旋结构域的背景下进行检查。然后，从这些研究中收集的数据将用于设计混合小型蛋白质，并检查这种方法是否导致催化活性增强。预计该项目将为稳定蛋白质的设计提供新的见解，这些蛋白质可以从事重要的生物分子相互作用并暴露于本地酶促功能。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响审查标准来评估NSF的法定任务。

项目成果

N -Aminoglycine and Its Derivatives Stabilize PPII Secondary Structure

N-氨基甘氨酸及其衍生物稳定 PPII 二级结构

• DOI: 10.1021/acs.orglett.3c01502
• 发表时间: 2023
• 期刊: Organic Letters
• 影响因子: 5.2
• 作者: Rajewski, Benjamin H.;Wright, Madison M.;Gerrein, Taylor A.;Del Valle, Juan R.
• 通讯作者: Del Valle, Juan R.

Total Synthesis of Pargamicin A

帕加霉素A的全合成

• DOI: 10.1021/acs.orglett.2c03861
• 发表时间: 2022
• 期刊: Organic Letters
• 影响因子: 5.2
• 作者: Elbatrawi, Yassin M.;Gerrein, Taylor;Anwar, Avraz;Makwana, Kamlesh M.;Degen, David;Ebright, Richard H.;Del Valle, Juan R.
• 通讯作者: Del Valle, Juan R.