Electrochemical Chemiluminescent Arrays & Emitters for Rapid Chemical Probe Iden

小分子文库和天然产物提取物的高通量筛选（HTS）是现代药物发现的重要组成部分。流行的HTS方法很大程度上依赖于基于荧光和FRET的传感方案，其充满了固有的限制，包括高成本和与某些物种的不相容性。鉴于绝大多数候选药物是通过HTS努力确定的，该研究计划的长期目标是开发更好的传感方法，可以在生理相关条件下快速识别先导治疗药物。该子项目的目标是建立强大的新平台和方法，可以检测生物分子结合现象。这些系统将有助于绘制新的生物信号通路，并确定小分子化学探针和治疗线索。基于我们在这一领域的初步工作和专业知识，我们确定了该计划的以下具体目标：（1）开发用于治疗性铅发现的基于ECL的电极微阵列;以及（2）开发用于无标记生物分子检测和蛋白质淘选的基于ECL的电极微阵列。这两个努力都是创新的，因为它们将允许在广泛的条件下使用通常与现代HTS方法不相容的化合物来探测蛋白质结合相互作用。这项研究意义重大，因为它将为蛋白质结合现象建立新的传感模式，为筛选小分子拮抗剂提供通用和强大的平台，并使蛋白质淘选实验得以进行。此外，通过在协作网络中发挥重要作用，该子项目不仅有助于定义新蛋白质， 不仅为治疗开发提供了靶点，而且还提供了鉴定命中化合物的手段，这些化合物可以被推进到新的化学探针中。

High-throughput screening (HTS) of small-molecule libraries and Natural product extracts is a crucial component of modern-day drug discovery. Popular HTS methods rely largely on fluorescence and FRETbased sensing protocols, which are fraught with inherent limitafions, which include high cost and incompatibility with certain species. Given that an overwhelming majority of drugs candidates are identified through HTS efforts, the long-term goal of this research program is the development of better sensing methods that can quickly identify lead therapeufics under physiologically relevant condifions. The objective of this subproject is the establishment of powerful new platforms and methods that can detect biomolecule binding phenomena. These systems will help map new biological signaling pathways, and identify smallmolecule chemical probes and therapeufic leads. Based on our inifial work and expertise in this area, we have identified the following specific aims for this program: (1) Development of ECL-based Electrode Microarrays for Therapeufic Lead Discovery; and (2) Development of ECL-based Electrode Microarrays for Label-Free Biomolecule Detecfion and Protein Panning. Both ofthese endeavors are innovative as they will permit protein binding interacfions to be probed under a broad array of condifions, using compounds that are often incompafible with modern HTS methods. The proposed research is significant because it will establish new sensing paradigms for protein binding phenomena, provide general and robust platforms to screen small-molecule antagonists, and enable protein-panning experiments to be pursued. Further, by funcfioning as an essenfial cog within a collaborative network, this subproject will not only help define new protein targets for therapeufic development, but also provide the means to identify hit compounds that can be advanced into new chemical probes.