Atomically Precise Nanoparticles with Multivalent Capabilities

具有多价功能的原子级精确纳米粒子

• 批准号: 9753274
• 负责人: Alexander Michael Spokoyny
• 金额: $ 36.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753274
• 关键词: 3-Dimensional; Address; Affect; Air; Benign; Binding; Biological; Biology; Chemicals; Chemistry; Complex; Defect; Development; Diagnostic; Dimensions; Disease; Elements; Engineering; Event; Exhibits; Gold; Hybrids; In Vitro; Lead; Ligands; Metals; Molecular; Nature; Oligonucleotides; Organism; Peptides; Positioning Attribute; Process; Property; Proteins; Research; Research Personnel; Statistical Distributions; Structure; System; Therapeutic; Time; Uncertainty; Viral; Work; base; biomacromolecule; combat; design; enhancing factor; functional group; improved; materials science; nanomaterials; nanoparticle; nanosystems; programs; receptor; small molecule; three dimensional structure; tool

Project Summary Unlike proteins and small-molecules, hybrid nanoparticle assemblies are never atomically precise and therefore have non-uniform composition and size. This fundamentally limits the researcher's ability to precisely engineer recognition and binding properties of these assemblies. This is especially true of a large class of hybrid noble metal nanoparticles including gold-based systems (AuNPs). Weak metal-ligand interactions contribute to a statistical distribution of defects and positional uncertainty of ligands around the metal core, limiting their molecular precision. Consequently, inherent polydispersity features of hybrid nanoparticles leads to their diminished selectivity when they are designed to target and bind biomacromolecules. Furthermore, under relatively benign conditions, weak metal-ligand interactions in the hybrid nanoparticles can result in scrambling events and ultimately degradation. Therefore, the status quo in the field largely centers on our inability to rationally address structure-function properties of hybrid nanomaterials. Our proposed effort can be characterized as a “nanoparticle total synthesis”, where we are utilizing a bottom-up approach for the synthesis of large hybrid molecules using atomically precise 3D inorganic clusters as rigid templates. Specifically, we propose a new strategy for building robust, atomically precise hybrid nanomolecules using air-stable inorganic clusters densely decorated with perfluoroaromatic functional groups. This strategy is very appealing given its similarity to the synthesis of AuNPs; however, in this case, the resulting structures maintain full atomic precision and exhibit dramatically improved stability due to the full covalency of the resulting systems. We will use this strategy for facile attachment of receptor building blocks and positioning these in three-dimensions with an atomic precision. For our studies, we will work on developing multivalent species capable of binding and sensing biomolecules under biologically relevant conditions. We will work to understand three-dimensional structures of our assemblies and how the size and dynamics in these systems affects “perfect” target binding. Atomic precision of these species will enable us to conduct structural studies to precisely pinpoint these interactions. We will study a cooperative binding of the peptide-grafted clusters with multiple sub-components of the viral entry machinery; and show how an atomically precise nanomolecules grafted with oligonucleotides can be evolved as binders using in vitro selection. Ultimately, our work will help to promote a thorough understanding of the design rules governing interactions between hybrid nanomaterials and biomolecules and elucidate the dominant factors that enhance specific inhibition of complex biomolecular targets. For the first time, combining elements of inorganic cluster chemistry, chemical biology and materials science we will enable researchers to create well-defined programmable nanosystems with unique capabilities for binding and sensing complex biomolecules.

项目摘要 与蛋白质和小分子不同，杂化纳米颗粒组装永远不会在原子上精确和 因此会有不均匀的成分和尺寸。这从根本上限制了研究人员准确地 工程师对这些组件的识别和绑定属性。尤其是对于一大批 混合贵金属纳米颗粒，包括基于金的体系(AuNPs)。弱金属-配体相互作用 有助于金属核周围的配位体的缺陷和位置不确定性的统计分布， 限制了它们的分子精确度。因此，杂化纳米颗粒固有的多分散性特征领先于 当它们被设计成靶向和结合生物大分子时，它们的选择性降低。此外， 在相对有利的条件下，杂化纳米颗粒中弱的金属-配体相互作用可以导致 混乱的事件和最终的退化。因此，该领域的现状主要集中在我们的 无法合理解决杂化纳米材料的结构-功能特性。 我们提出的努力可以被描述为“纳米粒子全合成”，我们利用一种 自下而上利用原子精密三维无机簇合物合成大分子杂化分子 作为刚性模板。具体地说，我们提出了一种新的策略，用于构建健壮的、原子精确的混合动力 纳米分子使用空气稳定的无机簇合物，稠密地装饰着全氟芳香官能团。 这一策略非常吸引人，因为它与AuNPs的合成相似；然而，在这种情况下， 最终得到的结构保持了完全的原子精度，并由于完全的 得到的体系的共价性。我们将使用这种策略来方便地连接受体构建块 并以原子的精度在三维中定位它们。对于我们的学习，我们将致力于开发 能够在生物相关条件下结合和感应生物分子的多价物种。我们会 努力了解我们组件的三维结构，以及这些组件中的大小和动力学 系统会影响“完美”的目标绑定。这些物种的原子精确度将使我们能够进行结构 精确定位这些相互作用的研究。我们将研究一种接枝肽的协同结合 带有病毒进入机制的多个子组件的集群；并展示了原子精确度如何 通过体外选择，嫁接了寡核苷酸的纳米分子可以进化为结合剂。 最终，我们的工作将有助于促进对以下设计规则的彻底理解 杂化纳米材料与生物分子的相互作用及其影响因素 对复杂生物分子靶标的特异性抑制。首次将无机簇合物的元素结合在一起 化学、化学生物学和材料科学，我们将使研究人员能够创造出明确的 具有结合和传感复杂生物分子的独特能力的可编程纳米系统。