New Generation of Mitochondrial Uncouplers for the Treatment of Metabolic DIsorders

用于治疗代谢紊乱的新一代线粒体解偶联剂

• 批准号: 10383829
• 负责人: Liliya Gabelev Khasin
• 金额: $ 34.09万
• 依托单位: EQUATOR THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383829
• 关键词: 2,4-Dinitrophenol; Address; Adenine Nucleotide Translocase; Adenine Nucleotides; Adult; Agonist; Animals; Area; Automobile Driving; Basal metabolic rate; Bioenergetics; Biological Assay; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cell Line; Cell membrane; Cells; Chemicals; Citric Acid Cycle; Clinical; Development; Diabetes Mellitus; Dinitrophenols; Dyslipidemias; Electron Transport; Electrophysiology (science); Energy Intake; Energy Metabolism; Epidemic; Fatty Liver; Generations; Genus Hippocampus; Glycolysis; Goals; Hepatocyte; Human; Hypertension; In Vitro; Individual; Inner mitochondrial membrane; Insulin Resistance; Knock-out; Lead; Libraries; Liver diseases; Measurement; Measures; Mediating; Medical; Metabolic Diseases; Metabolic syndrome; Mitochondria; Modeling; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR gamma; Patch-Clamp Techniques; Pathway interactions; Pharmaceutical Preparations; Physiological; Plant Roots; Positioning Attribute; Property; Proteins; Regulation; Respiration; Risk; Running; Safety; Series; Societies; Specificity; Testing; Therapeutic; Thermogenesis; Tissues; Weight Gain; chemical property; counterscreen; cytotoxicity; drug development; extracellular; high throughput screening; improved; inhibitor/antagonist; insight; insulin sensitizing drugs; metabolic rate; mouse model; novel; patch clamp; professor; ratiometric; side effect; small molecule; uncoupling protein 1

Project Summary/Abstract Metabolic syndrome (MetS), a constellation of medical conditions that includes obesity, type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and dyslipidemia, creates a major burden for individuals and society. MetS is caused by insulin resistance and obesity, and a drug that could reverse these two conditions would transform its treatment. Unfortunately, no safe and effective medication with such properties exists. Equator Therapeutics is developing a first-in-class drug that will increase the resting metabolic rate by activating the native pathways for mitochondrial H+ leak and thermogenesis. This drug will correct the root cause of metabolic disorders—the imbalance between excess caloric intake and limited energy expenditure— and is expected to be highly effective at reversing obesity and insulin resistance. Until recently, development of such drug was impossible due to a very limited understanding of the mechanisms of the mitochondrial H+ leak. Instead, protonophores that indiscriminately increase H+ leak not only in mitochondria but all cell membranes, were used, leading to undesirable side effects. In contrast, our drug will activate H+ leak specifically in mitochondria via the physiologically regulated native H+ leak pathways mediated by uncoupling proteins and is expected to be much safer. The development of this drug is enabled by our recent discoveries concerning the molecular mechanisms of the mitochondrial H+ leak. In Specific Aim 1, we will identify a set of diverse drug-like compounds that selectively activate a protein target natively responsible for the mitochondrial H+ leak. Importantly, these compounds will have no protonophoric activity. We have selected a library of ~67,000 small molecules with desirable chemical properties specific to our target. We will screen this library for hits that increase mitochondrial H+ leak using new high-throughput mitochondrial assays consisting of a primary screen and counter-screen to remove false positives. Compounds that pass both rounds of high- throughput screening will be validated by direct measurement of the H+ current via our target protein using mitochondrial patch-clamp electrophysiology. Additional patch-clamp studies in the plasma membrane will further select only those of them that lack any protonophoric activity. In Specific Aim 2, we will determine the effects of the novel activators of the native mitochondrial H+ leak pathways on the bioenergetics of intact human cells in vitro. We will primarily focus on the ability of our compounds to stimulate uncoupled respiration, the parameter reflecting their ability to activate mitochondrial H+ leak and thermogenesis in intact cells. Other parameters such as the respiration capacity of the cell, activity of the glycolytic pathways, and the intracellular ATP level will also be assessed. Finally, cytotoxicity assays will be performed. Successful accomplishment of these aims will generate a set of chemically diverse lead compounds that we will bring forward to animal studies with the goal of developing a safe drug to transform treatment of MetS.

项目摘要/摘要 代谢综合征(METS)，一系列的医疗状况，包括肥胖、2型糖尿病、肥胖 肝脏、高血压、心血管疾病和血脂异常，对个人和 社会。甲硫氨酸是由胰岛素抵抗和肥胖引起的，一种可以逆转这两种情况的药物 会改变它的治疗方式。不幸的是，目前还没有安全有效的药物来治疗这种物质。 赤道治疗公司正在开发一种一流药物，该药物将通过以下方式提高静息代谢率 激活线粒体H+泄漏和产热的天然途径。这药能正本清源 代谢紊乱的原因--过多的卡路里摄入和有限的能量消耗之间的失衡-- 有望在逆转肥胖和胰岛素抵抗方面非常有效。直到最近， 由于对线粒体H+泄漏机制的了解非常有限，这种药物是不可能的。 相反，不分青红皂白地增加H+的原生团不仅在线粒体中泄漏，而且在所有细胞膜中泄漏， 被使用了，导致了不良的副作用。相反，我们的药物会激活H+泄漏 解偶联蛋白和IS介导的生理调节的天然H+泄漏途径 预计会安全得多。这种药物的开发是由我们最近关于 线粒体H+泄漏的分子机制。在具体目标1中，我们将确定一套不同的 类药物化合物，选择性地激活天然负责的蛋白质靶标 线粒体H+渗漏。重要的是，这些化合物将不会有原激动剂活性。我们已经选择了一个 约67,000个小分子的库，这些小分子具有特定于我们的目标的理想的化学性质。我们会放映这个 使用新的高通量线粒体分析增加线粒体H+泄漏的HITS文库，包括 用于去除假阳性的主屏幕和反屏幕。通过两轮高- 通过使用我们的目标蛋白直接测量H+电流来验证吞吐量筛选 线粒体膜片钳电生理学。质膜上的其他膜片钳研究将 此外，只选择那些缺乏任何原激动素活性的。在具体目标2中，我们将确定 天然线粒体H+泄漏通路的新型激活剂对生物能量学的影响 完整的人体细胞在体外。我们将主要关注我们的化合物刺激解偶联的能力 呼吸作用，反映他们激活线粒体H+泄漏和生热能力的参数 细胞。其他参数如细胞的呼吸能力，糖酵解途径的活性，以及 细胞内的三磷酸腺苷水平也将被评估。最后，将进行细胞毒性试验。成功 这些目标的实现将产生一系列化学上不同的先导化合物，我们将带来 期待进行动物研究，目标是开发一种安全的药物来改变METS的治疗。