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Protein Chemistry

蛋白质化学

基本信息

批准号：
10552380
负责人：
Ronald T Raines
金额：
$ 47.49万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

项目摘要

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.

项目摘要/摘要现存药典中的大多数药物都是小分子。这些小分子中有一半起作用作用于细胞外靶点，一半作用于细胞内靶点。少数药物是蛋白质，而且实际上，所有这些蛋白质都是抗体、激素或作用于细胞外靶点的酶。这个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。该计划利用了新的化学反应性，使用调谐的重氮化合物来使蛋白质的羧基在水中酯化。由此产生的酯化蛋白质类似于小的- 能够穿透人类细胞质膜的分子前药。酯水解法由细胞内酯酶催化，使修饰无迹，避免对适当的任何妥协功能。“蛋白质酯化”是一幅未知的图景。因此，工作将于#年开始。探索酯化蛋白质的基本属性，包括它们的细胞摄取和细胞酯酶水解酯的酶学。将招募特定的系统来评估这种交付方法的普遍性，并提供了发现的机会。特别是，酯化反应将被用来传递特定的蛋白质，引起细胞毒性或肿瘤抑制，或控制基因组正在编辑。递送策略还将用于锚定寡核苷酸和其他有益部分并概括了细胞蛋白质的选择性降解。这些广袤而遥远的- 达成的努力将在生物医学、化学生物学和相关领域产生重大影响的进展。