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Cyclopropenones to assemble, analyze, and activate biomolecules

用于组装、分析和激活生物分子的环丙烯酮

基本信息

批准号：
10061611
负责人：
Jennifer Prescher
金额：
$ 27.58万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

项目摘要

Project Summary Chemical tools can provide unique insights into biomolecule structure and function. Included in this group are bioorthogonal chemical reporters—biocompatible functional groups that can target diverse classes of biomolecules and be selectively ligated with various probes. These reporters and reactions enable biomolecules to be analyzed in their native environments. Despite their past successes and continued potential, most chemical reporters have been slow to transition to biological studies and the scientific community at large. Many reporters are too large or insufficiently stable for routine cellular use, or lack chemical versatility. The long-term goal of our work is to develop robust, easy-to-access chemical probes for tracking and controlling biomolecules in cells and tissues. The objective of this application is to develop one reagent—cyclopropenone—as a general and versatile chemical reporter. Cyclopropenones harbor unique features for biological application. They are small, reactive with bioorthogonal soft nucleophiles (e.g., phosphines), and highly tunable. In addition to tagging biomolecules, cyclopropenones can be used to control biomolecule function via phosphine-mediated crosslinking and decaging chemistries. Thus, from a single cyclopropenone unit, one—in theory—can assemble, analyze, and activate biomolecules of interest. The versatility and accessibility of such reagents can provide a “one-stop-shop” for tool users, bringing chemical probes more rapidly into the hands of non-specialists. Guided by strong preliminary data, our work will encompass the following specific aims: 1) Tune cyclopropenone reactivity for broad-spectrum biomolecule analyses; (2) Exploit “latent” cyclopropenone reactivities for biomolecule assembly; and (3) Establish chemical triggers of biomolecule function. Under the first aim, we will examine the scope of the cyclopropenone-phosphine ligation, and identify scaffolds with suitable stability and reactivity profiles. In the second aim, we will capitalize on “latent” cyclopropenone reactivities to assemble biomolecule conjugates. In the third aim, we will develop cyclopropenone triggers that can be used to crosslink and activate biomolecules of interest. Our approach is highly innovative, as it capitalizes on a unique reaction mechanism to access multi-functional bioorthogonal properties. The proposed research is significant, as it will provide versatile, easy-to-use chemical tools that are applicable to a broad spectrum of biomedical research. The probes will also enable experiments not possible with existing toolsets. Additionally, like other chemical technologies, the proposed reagents will likely inspire new discoveries in diverse fields.

项目概要化学工具可以提供对生物分子结构和功能的独特见解。包含在该组中是生物正交化学报告基因——生物相容性官能团，可以针对不同类别的生物分子并与各种探针选择性连接。这些记者和反应使在其原生环境中进行分析的生物分子。尽管他们过去取得了成功并继续潜力，大多数化学记者在转向生物研究和科学领域进展缓慢整个社区。许多记者对于常规细胞使用来说太大或不够稳定，或者缺乏化学多功能性。我们工作的长期目标是开发强大的、易于访问的化学探针用于跟踪和控制细胞和组织中的生物分子。该应用程序的目标是开发一种试剂——环丙烯酮——作为通用且多功能的化学报告剂。环丙烯港生物应用的独特功能。它们很小，可与生物正交软亲核试剂发生反应（例如磷化氢），并且高度可调。除了标记生物分子外，还可以使用环丙烯酮通过膦介导的交联和脱腐化学来控制生物分子功能。因此，从一个理论上，单个环丙烯酮单元可以组装、分析和激活感兴趣的生物分子。此类试剂的多功能性和可获取性可以为工具用户提供“一站式服务”，化学探针更快地进入非专业人士手中。在强有力的初步数据的指导下，我们工作将涵盖以下具体目标：1）调整环丙烯酮反应性以实现广谱生物分子分析； (2) 利用“潜在”环丙烯酮反应性进行生物分子组装；和（3）建立生物分子功能的化学触发因素。在第一个目标下，我们将审查环丙烯酮-膦连接，并鉴定具有合适稳定性和反应性特征的支架。在第二个目标，我们将利用“潜在”环丙烯酮反应性来组装生物分子缀合物。在第三个目标中，我们将开发可用于交联和活化的环丙烯酮触发器感兴趣的生物分子。我们的方法具有高度创新性，因为它利用了独特的反应访问多功能生物正交特性的机制。拟议的研究意义重大，因为它将提供通用、易于使用的化学工具，适用于广泛的生物医学研究。这些探针还将使现有工具集无法进行的实验成为可能。另外，像与其他化学技术相比，所提出的试剂可能会激发不同领域的新发现。