Protein-Induced Self-Assembly and Disassembly of Nanostructures Based on Oligo

基于Oligo的蛋白质诱导纳米结构自组装和分解

• 批准号: 10581638
• 负责人: Sankaran Thayumanavan
• 金额: $ 51.3万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581638
• 关键词: Biology; Cells; Cellular Membrane; Custom; Encapsulated; Environment; Event; Goals; Guidelines; Hydrophobicity; Imprisonment; Molecular; Nanostructures; Oligonucleotides; Oxidation-Reduction; Polymers; Process; Proteins; Research; Stimulus; Structure; System; Temperature; design; molecular assembly/self assembly; nanoassembly; non-Native; novel; programs; response; self assembly; small molecule; structural determinants; treatment response

PROJECT SUMMARY / ABSTRACT This proposal describes a concerted approach to the design, synthesis, and study of novel self- assembling molecules that are responsive to specific proteins. We take two complementary approaches. First, we develop design guidelines where proteins act as the trigger to deconstruct a higher order assembly to a lower order one (protein-responsive supramolecular disassembly). In this process, the assemblies transform from an effective host for hydrophobic small molecules to an ineffective one, which has implications in developing precise therapeutic responses to protein imbalances. In the second approach, we propose to develop molecular design guidelines that program a non-assembling polymer to transform into a higher order assembly in response to proteins (protein-templated self-assembly). The resultant nanoassemblies are programmed to release these encapsulated proteins in their pristine form in the presence of a specific biologically-relevant stimulus or due to a combination of such stimuli. Such a strategy will offer the ability to traffic proteins across a cellular membrane and release them inside cells, which has implications in several unmet challenges in biomedicine. In the protein-responsive supramolecular disassembly approach, we propose to develop versatile supramolecular assemblies that disassemble in response to specific proteins as stimuli. There have been great advances in stimuli-sensitive supramolecular assemblies. However, these have primarily focused on systems that respond to changes in factors such as pH, temperature, or redox conditions, which are secondary imbalances in biology. The most direct and primary indicator of imbalance in biology involves change in protein activity. Therefore, generating supramolecular assemblies that respond to proteins is exciting. Our primary objective is to obtain a better understanding of the structural factors that control the assembly/disassembly events in response to specific combinations of enzymatic and non-enzymatic proteins. In the protein-templated self-assembly approach, the templating proteins are incarcerated as guests into a matrix of host polymers. The resultant nanoassemblies are programmed to release these encapsulated proteins in their pristine form in the presence of a specific biologically-relevant stimulus or due to a combination of such stimuli. A key goal of the proposed research is to develop this into a new supramolecular platform that is useful for a broad range of soluble proteins, a capability that does not currently exist. The primary premise of the proposed research then is to develop a fundamental framework for custom-designing such supramolecular assemblies that can predictably encapsulate a protein, turn its function off, protect it from denaturation in non-native environments, and regain its native structure and function in response to a stimulus that is specific to the target environment. We will identify the structural factors that underlie the formation of these programmable molecular assemblies.

项目摘要 /摘要 该提案描述了新型自我的设计，综合和研究的一致方法 组装对特定蛋白质响应的分子。我们采用两种补充方法。第一的， 我们制定了设计指南，其中蛋白质是将高阶组件解构为一个触发的触发因素 较低阶（蛋白质反应性超分子拆卸）。在此过程中，组件变换 从有效的疏水性小分子到无效的宿主，这对 对蛋白质失衡产生精确的治疗反应。在第二种方法中，我们建议 制定分子设计指南，以编程非组装聚合物以转化为更高阶段 响应蛋白质的组装（蛋白质 - 模拟自组装）。由此产生的纳米组件是 编程以在特定的情况下以原始形式释放这些封装的蛋白质 与生物学相关的刺激或由于这种刺激的组合。这样的策略将提供能力 跨细胞膜的交通蛋白并将其释放在细胞内，这在几个 生物医学中未满足的挑战。 在蛋白质反应性超分子拆卸方法中，我们建议开发多功能 响应特定蛋白作为刺激而拆卸的超分子组件。有 刺激敏感的超分子组件的巨大进步。但是，这些主要集中于 响应pH，温度或氧化还原条件等因素的变化的系统， 生物学的次要失衡。生物学不平衡的最直接和主要指标涉及 蛋白质活性的变化。因此，生成对蛋白质反应的超分子组件是 令人兴奋。我们的主要目标是更好地了解控制控制的结构因素 响应酶促和非酶蛋白的特定组合的组装/拆卸事件。 在蛋白质 - 模拟的自组装方法中，将模板蛋白被监禁为客人 寄主聚合物的矩阵。将最终的纳米组件编程为释放这些封装 在特定与生物学与生物学相关的刺激的情况下，以原始形式的蛋白质或 这种刺激的组合。拟议研究的关键目标是将其发展为新的超分子 平台可用于广泛的可溶性蛋白质，这是当前不存在的能力。这 然后，拟议研究的主要前提是开发一个基本框架以定制设计 这种超分子组件可以预测地封装蛋白质，关闭其功能，保护它 从非本地环境中的变性，并恢复其本地结构和功能，以响应 特定于目标环境的刺激。我们将确定基于的结构性因素 这些可编程分子组件的形成。