Atomically Precise Nanoparticles with Multivalent Capabilites

具有多价功能的原子级精确纳米粒子

• 批准号: 9919320
• 负责人: Alexander Michael Spokoyny
• 金额: $ 6.95万
• 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/9919320
• 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，混合纳米颗粒组装从来不是原子级精确的， 因此具有不均匀的组成和尺寸。这从根本上限制了研究人员精确地 工程师识别和绑定这些组件的属性。这是特别真实的一大类 混合贵金属纳米颗粒，包括基于金的系统（AuNP）。弱金属-配体相互作用 有助于缺陷的统计分布和金属核周围配体的位置不确定性， 限制了它们的分子精确度。因此，混合纳米颗粒的固有多分散性特征导致 当它们被设计为靶向和结合生物大分子时，它们的选择性降低。此外，委员会认为， 在相对温和的条件下，混合纳米颗粒中弱的金属-配体相互作用可导致 扰乱事件并最终退化。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。 我们所提出的努力可以被描述为“纳米颗粒全合成”，其中我们利用 使用原子级精确的3D无机团簇合成大杂化分子的自底向上方法 as rigid刚性template模板.具体来说，我们提出了一种新的策略，用于构建鲁棒的，原子精确的混合 纳米分子，其使用用全氟芳族官能团密集修饰的空气稳定无机簇。 考虑到其与AuNP的合成的相似性，该策略是非常有吸引力的;然而，在这种情况下， 所得的结构保持完全原子精度，并由于完全原子化而表现出显著改善的稳定性。 结果系统的共价性。我们将使用这种策略来轻松连接受体构建模块 并以原子级的精度在三维空间中定位。为了我们的研究，我们将致力于开发 能够在生物学相关条件下结合和感测生物分子的多价物质。我们将 努力了解我们的组件的三维结构，以及这些组件的大小和动力学是如何变化的。 系统影响“完美的”目标结合。这些物种的原子精度将使我们能够进行结构 研究来精确地确定这些相互作用。我们将研究肽嫁接的协同结合 集群与多个子组成部分的病毒进入机制，并显示如何原子精确 用寡核苷酸接枝的纳米分子可以使用体外选择进化为结合剂。 最终，我们的工作将有助于促进对管理 混合纳米材料和生物分子之间的相互作用，并阐明增强 对复杂生物分子靶点的特异性抑制。第一次将无机团簇元素 化学，化学生物学和材料科学，我们将使研究人员能够创造明确的 可编程纳米系统具有独特的能力，用于结合和传感复杂的生物分子。