Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance

摘要 有必要开发具有不同于现有药物的作用机制的糖尿病药物。 脂肪细胞功能缺陷导致全身性胰岛素抵抗和肥胖相关糖尿病的发病。这个 肥大的脂肪细胞处理糖脂和分泌胰岛素敏感型脂肪因子的能力 严重受损，导致高血糖、高脂血症、胰岛素抵抗、炎症、 以及脂肪沉积在肝脏等组织中，从而抑制胰岛素的作用。可以恢复这些信息的代理 缺陷和恢复组织间的自然脂肪分配是对人类有用的胰岛素增敏剂。这个 该项目解决的关键挑战是新分子的识别和治疗验证 可通过药物调节修复脂肪细胞缺陷和恢复胰岛素信号转导的途径 肝脏和其他组织。 我们的多学科团队将通过将尖端的表型筛选和 化学蛋白质组学技术，在脂肪组织、肝脏生物学和脂类代谢方面拥有深厚的专业知识。 我们开发了将表型筛选与化学蛋白质组学相结合的创新策略，以 简化了生物活性小分子蛋白质靶标的识别，我们最初将其应用于 丝氨酸水解酶家族的酶，但最近已扩展到蛋白质组范围的研究。 我们建议用我们新的强大的平台来补充我们最初专注于丝氨酸水解酶的方法 将表型筛选和化学生物学相结合，实现快速、系统和蛋白质组范围的分析 发现新陈代谢靶点。通过筛选独特的小分子文库寻找所需的表型 脂肪细胞和肝细胞以一种公正的方式，我们将在串联的生理相关蛋白质 和化学工具来干扰这些蛋白质的功能，以加快它们的功能注释和 糖尿病和非酒精性胰腺炎的疗效验证。在这个过程中，我们将创造一流的化学探测器和 研究关键代谢途径的遗传模型，这些模型将分发给更大的研究社区。 我们的尖端化学生物学平台从根本上扩展了可作为靶点的蛋白质组部分 用小分子。这些工具在驱动糖尿病的核心问题上的应用赋予了这个项目 具有无与伦比的潜力，可以发现治疗糖尿病及相关疾病的新靶点。

Abstract There is a need to develop diabetes drugs with a mechanism of action distinct from that of established agents. Defects in adipocyte function drive the onset of systemic insulin resistance and obesity-linked diabetes. The ability of hypertrophied adipocytes to dispose of glucose and lipids and secrete insulin-sensitizing adipokines is severely compromised and this contributes to hyperglycemia, hyperlipidemia, insulin resistance, inflammation, and lipid deposition in tissues such as liver where it dampens insulin action. Agents that can revert these defects and restore natural lipid partitioning amongst tissues are useful insulin sensitizers in humans. The critical challenge that this project addresses is the identification and therapeutic validation of new molecular pathways that can be pharmacologically modulated to revert adipocyte defects and restore insulin signaling in liver and other tissues. Our multidisciplinary team will achieve this goal by combining cutting-edge phenotypic screening and chemoproteomic technologies, with deep expertise in adipose tissue and liver biology and lipid metabolism. We have developed innovative strategies that integrate phenotypic screening with chemoproteomics to streamline the identification of protein targets of bioactive small molecules, which we initially applied to enzymes of the serine hydrolase family, but have more recently extended for proteome-wide investigations. We propose to complement our initial serine hydrolase-focused approach with our new powerful platforms for integrated phenotypic screening and chemical biology to enable the rapid, systematic, and proteome-wide discovery of metabolism targets. By screening unique libraries of small-molecules for desirable phenotypes in adipocytes and hepatocytes in an unbiased manner, we will identify in tandem physiologically relevant proteins and chemical tools to perturb the function of these proteins to expedite their functional annotation and therapeutic validation in diabetes and NASH. In the process, we will create first-in-class chemical probes and genetic models to study key metabolic pathways that will be distributed to the larger research community. Our cutting-edge chemical biology platforms radically expand the portion of the proteome that can be targeted with small molecules. Application of these tools to the central problem that drives diabetes endows this project with unparalleled potential to discover new targets to treat diabetes and associated conditions.