Robust Sequence-defined Nanocages with Protein-mimetic Cavities

项目总结/摘要 模仿蛋白质样腔和功能需要精确地组织表面基团， 多孔支架以协调一致的方式发挥作用。在这里，我们建议完全生成 用于蛋白质的选择性、多价识别和催化的序列定义的坚固纳米笼 蛀牙基于PI在超分子，有机和计算方面独特的跨学科专业知识， 化学，主要目标是创造策略，设计和合成完全序列定义的 纳米笼作为用于感测生物分子的人工受体（例如，脑啡肽）和选择性 人造酶（例如，用于肽的位点选择性修饰）。我们将指导内面体的定位 官能团（例如，单肽、二肽或三肽）与手性的、序列限定的共价模板（例如， 序列限定的肽树状聚合物和α-螺旋肽），其将它们的外部氨基酸转移到 以立体控制的方式改变纳米笼的内面位置。Schneebeli实验室合成了 特征在于构建序列定义的纳米笼所需的坚固的、腙连接的纳米笼。这些 纳米笼已经成功地应用于小分子的受体， 聚合催化剂，这为提出的选择性神经肽识别和位点- 选择性催化我们将追求两个平行的途径来创建完全序列定义的纳米笼。在 项目1，我们将模板纳米笼形成直接在序列定义的方式，组装 用腙键（其在酸性条件下是可逆的）形成纳米笼，然后切出模板。 在项目2中，我们将立体选择性地官能化预先形成的[8+12]-纳米笼（用一种新的， 基于环三聚的合成）在α-螺旋肽模板和平衡亚胺键的帮助下， 然后还原亚胺键并切掉模板。本研究在概念上新颖， 方法，表征和应用，因为（i）完全序列定义的不对称纳米笼 代表了人工分子受体和人工酶的当前研究的相当大的转变，（ii） 腙连接的纳米笼和基于环三聚的纳米笼合成（在Schneebeli 组）是获得能够容纳大的和化学上坚固的纳米笼框架的有力方法。 多达12个具有完整序列定义的内面官能团，以及（iii）创建稳健的蛋白质模拟物 空腔可能最终在基础结构和机械知识方面产生许多进步， 人工受体/人工酶设计。这项研究意义重大，因为它将使合成 化学家独立地控制多孔纳米笼的内部位置，最终提供新的 快速检测生物分子和催化新的立体选择性化学物质的机会和方法 反应的治疗发展。

PROJECT SUMMARY/ABSTRACT Mimicking protein-like cavities and functions requires to precisely organize surface groups on well-defined, porous scaffolds to function in a concerted and orchestrated manner. Here, we propose to generate fully sequence-defined robust nanocages for selective, multivalent recognition and catalysis reminiscent of protein cavities. Building on the PI’s unique interdisciplinary expertise in supramolecular, organic, and computational chemistry, the primary objective is to create strategies to design and synthesize fully sequence-defined nanocages as artificial receptors for sensing biomolecules (e.g., enkephalins in the brain) and as selective artificial enzymes (e.g., for site-selective modification of peptides). We will direct the positioning of the endohedral functional groups (e.g., mono-, di-, or tripeptides) with chiral, sequence-defined covalent templates (e.g., sequence-defined peptide dendrimers and a-helical peptides), which will transfer their outer amino acids onto the endohedral sites of the nanocages in a stereocontrolled manner. The Schneebeli lab has synthesized and characterized robust, hydrazone-linked nanocages required to bulid the sequence-defined nanocages. These nanocages have been successfully applied as receptors for small molecules, and as size-selective polymerization catalysts, which lays the foundation for the proposed selective neuropeptide recognition and site- selective catalysis. We will pursue two parallel avenues to create the fully sequence defined nanocages. In Project 1, we will template nanocage formation directly in a sequence-defined manner, assembling the nanocages with hydrazone bonds (which are reversible under acidic conditions) and then cut out the templates. In Project 2, we will stereoselectively functionalize preformed [8+12]-nanocages (created with a novel, cyclotrimerization-based synthesis) with the help of a-helical peptide templates and equilibrating imine bonds, and then reduce the imine bonds and cut out the templates. This research is novel in the concept, synthetic approach, characterization, and applications, because (i) fully sequence-defined asymmetric nanocages represent a considerable shift in the current research of artificial molecular receptors and artificial enzymes, (ii) hydrazone-linked nanocages and cyclotrimerization-based nanocages syntheses (pioneered in the Schneebeli group) are powerful approaches to access large and chemically-robust nanocage frameworks capable of holding up to 12 endohedral functional groups with full sequence definition, and (iii) the creation of robust, protein-mimetic cavities may ultimately yield numerous advances in both fundamental structural and mechanistic knowledge of artificial receptor/artificial enzyme design. The proposed research is significant, because it will enable synthetic chemists to independently control the endohedral sites of porous nanocages, ultimately offering new opportunities and approaches to rapidly sense biomolecules and catalyze new, stereoselective chemical reactions for therapeutics development.