Automated Synthesizer for Diversity-Oriented Synthesis of Peptides and Peptoids

该申请旨在为复杂生物活性分子的自动化合成提供资金。肽和相关的合成类似物是一类线性分子，其由在顺序连接步骤中连接在一起的各种结构单元构建而成。通过改变结构单元在序列中的位置，可以产生具有不同性质的不同分子的惊人多样性。这些步骤是重复的，迭代的，通常非常耗时。用传统的人工合成方法制造一个这样的分子需要一整天的时间。化学已经完善到可以通过自动化系统完成的程度。所要求的自动化平行合成仪可以使用超过25种不同的构建模块和试剂，加热，搅拌，过滤和液体处理都是自动完成的。制造每个分子所需的数十个步骤可以在没有人为干预的情况下完成，计算机控制的系统可以在单独的反应容器中同时制造六个这样的分子。霍夫小组提出了这些肽和人工肽样分子的创新用途。平行制备的许多不同的肽化合物将被并入杂合结构中，所述杂合结构还包括结合元件（核心结合口袋）并且有时包括传感元件（在结合时改变颜色的分子）。我们的目标是使有效的和选择性的分子亲和试剂，将目标和结合到其他分子。这些新型结合试剂的未来应用包括创建新的蛋白质和代谢物结合研究工具，生物流体样品中非法药物的直接光学检测，药物毒性的逆转以及新型诊断的创建。** 霍夫小组的研究项目依赖于老一代的肽合成仪，该合成仪在2018年11月灾难性地失败了。所要求的新系统既可以替代这一关键基础设施，也可以进行关键升级，因为它具有在全自动化过程中同时生产6种化合物的尖端能力。这种并行制造化合物的能力对于霍夫小组在多样性驱动的化学中的新方向至关重要。

This application proposes to fund a cutting-edge system for automated synthesis of complex bio-active molecules. Peptides and related synthetic analogs are classes of linear molecules built up from various building blocks that are attached together in sequential connective steps. By varying which building blocks are in which position in the sequence, a staggering diversity of different molecules with different properties can be created. These steps are repetitive, iterative, and normally incredibly time consuming. It would take a full day to make one such molecule by conventional manual synthesis methods. The chemistry has been perfected to the point that they can done by automated systems. The requested automated parallel synthesizer can use more than 25 distinct building blocks and reagents, with heating, agitation, filtrations, and liquids handling all done robotically. The dozens of steps that are needed to make each molecule can be done without human intervention, and the computer-controlled system can make six such molecules at the same time in separate reaction vessels.******The Hof group propose innovative uses for these peptides and artificial peptide-like molecules. The many different peptidic compounds that are made in parallel will be incorporated into hybrid structures that also include binding element (a core binding pocket) and that sometimes include a sensing element (molecules that change color upon binding). We aim to make potent and selective molecular affinity reagents that will target and bind to other molecules. Future applications for these many novel binding reagents include the creation of new protein- and metabolite-binding research tools, the direct optical detection of illicit drugs in biofluid samples, the reversal of drug toxicity, and the creation of new kinds of diagnostics. ******The Hof group's research program was reliant on an older-generation peptide synthesizer, which catastrophically failed in November 2018. The new system that is requested offers both a replacement of this critical infrastructure, and also a key upgrade in that it has the cutting-edge ability to make 6 compounds at the same time in a fully automated process. This ability to make compounds in parallel is critical for the Hof group's new directions in diversity-driven chemistry.**