Protein Chemistry

项目概要/摘要 现存药典中的大多数药物都是小分子药物。这些小分子中有一半 作用于细胞外靶点，一半作用于细胞内靶点。少数药物是蛋白质， 实际上所有这些蛋白质都是作用于细胞外靶点的抗体、激素或酶。的 拟议的研究计划将赋予蛋白质进入细胞并作用于细胞内的能力 目标的该计划利用新的化学反应性，使用调谐重氮化合物， 使蛋白质羧基在水中变性。所产生的酯化蛋白质类似于小- 分子前药，使其能够穿过人细胞的质膜。酯水解 由细胞内酯酶催化的修饰使得修饰无痕，避免了对适当的修饰的任何损害。 功能“蛋白质酯化”有一个未知的景观。因此，工作将开始， 探索酯化蛋白质的基本属性，包括它们的细胞摄取机制， 细胞酯酶水解酯的酶学。将采用具体的系统来评估 这种交付方法的一般性，并提供发现的机会。特别是酯化反应 将被用于递送引起细胞毒性或肿瘤抑制的特定蛋白质，或控制基因组 编辑.该递送策略还将用于锚寡核苷酸和其它有益部分 并概括了细胞蛋白质的选择性降解。这些广阔而遥远的- 达成的努力将在生物医学，化学生物学和相关领域提供高影响力的进步。

PROJECT SUMMARY/ABSTRACT The majority of drugs in the extant pharmacopeia are small molecules. Half of those small molecules act on extracellular targets, and half act on intracellular targets. A minority of drugs are proteins, and virtually all of those proteins are antibodies, hormones, or enzymes that act on extracellular targets. The proposed research program will endow proteins with the ability to enter cells and act on intracellular targets. The program takes advantage of new chemical reactivity that uses tuned diazo compounds to esterify protein carboxyl groups in water. The resulting esterified proteins are analogous to small- molecule prodrugs in enabling traversal of the plasma membrane of human cells. Ester hydrolysis catalyzed by intracellular esterases makes the modifications traceless, avoiding any compromise to proper function. “Protein esterification” has an uncharted landscape. Accordingly, the work will begin by exploring fundamental attributes of esterified proteins, including their mechanism of cellular uptake and the enzymology of ester hydrolysis by cellular esterases. Specific systems will be enlisted to assess the generality of this delivery method and provide opportunities for discovery. In particular, esterification will be used to deliver particular proteins that elicit cytotoxicity or tumor suppression, or control genome editing. The delivery strategy will also be used to anchor oligonucleotides and other beneficial moieties on the cell surface and generalize the selective degradation of cellular proteins. These broad and far- reaching efforts will provide high-impact advances in biomedicine, chemical biology, and allied fields.