Therapeutic Mitochondrial Uncouplers

治疗性线粒体解偶联剂

• 批准号: 10185467
• 负责人: Webster L Santos
• 金额: $ 57.61万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185467
• 关键词: 2,4-Dinitrophenol; Address; Affect; Animal Model; Benchmarking; Bioavailable; Biological Assay; Biopsy; Bypass; Caymans; Cell membrane; Characteristics; Chemicals; Cirrhosis; Clinic; Clinical; Clinical Trials; Data; Diet; Drug Kinetics; Ensure; Environment; Etiology; FDA approved; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Goals; Hepatic; High Fat Diet; Human; Hyperthermia; Image; In Vitro; Inflammation; Inner mitochondrial membrane; Laboratories; Liver Failure; Liver diseases; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Mus; Nature; Non-Rodent Model; Oral; Oxidative Stress; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase III Clinical Trials; Physiological; Population; Primary carcinoma of the liver cells; Process; Production; Property; Proteins; Protons; Reactive Oxygen Species; Research; Research Personnel; Safety; Source; Specificity; Streptozocin; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; alkalinity; clinically relevant; design; efficacious treatment; efficacy validation; hepatocyte injury; improved; in vivo; in vivo evaluation; innovation; islet amyloid polypeptide; liver inflammation; mesoxalonitrile; metabolic rate; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; oxidation; phase III trial; phenylhydrazone; preservation; prevent; programs; protein transport; response; scaffold; screening; side effect; small molecule; success; tool

PROJECT SUMMARY The goal of this project is to develop small molecule mitochondrial uncouplers for the treatment of non- alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD). Approximately 26 million people (~6-8% of US population) are affected by NASH, and more than 30% of patients with NASH- related cirrhosis will die from liver failure or hepatocellular cancer. There are currently no FDA-approved drugs to treat NASH and the top drugs in clinical trials suffer from ineffectiveness or have unwanted side effects. NASH is characterized by fat accumulation in the liver, inflammation, and tissue remodeling. Mitochondrial uncouplers have strong potential as NASH therapeutics by the nature of their mode of action targeting fat accumulation and oxidative stress. Mitochondrial uncouplers transport protons from the mitochondrial intermembrane space into the matrix bypassing ATP synthase. This process increases fat oxidation and decreases mitochondrial reactive oxygen species production; thereby, directly targeting two pathways that underlie NASH pathophysiology that drive inflammation and the fibrogenic response. Our laboratories have recently discovered mitochondria- selective, safe, and orally bioavailable mitochondrial uncouplers that have wide therapeutic window. Proof-of- principle studies in an accelerated mouse model of NASH (STAM model) achieved the FDA benchmark for approval of a NASH therapeutic by decreasing the NAFLD Activity Score (NAS) by 2 points, with at least one point coming from two different NAS criteria, and with no worsening of fibrosis. These strong preliminary data support a medicinal chemistry program to improve the drug-like properties of the molecules (Aim 1) and validate molecules in a more physiologically and clinically relevant mouse model of NASH involving Amylin diet (Aim 2). The major innovation of our program is the discovery of novel chemical scaffolds that have different levels of mitochondrial uncoupling capacity that are safe and self-limiting. As there are currently no drugs with a mitochondrial uncoupling as the primary mode of action in the clinic, our program could be the first to deliver mitochondrial uncouplers for the treatment of NASH. Indeed, this project addresses a critical need and will make significant contribution to data supporting the validity of modulating mitochondrial uncoupling for safe and efficacious treatment of NASH.

项目总结 本项目的目标是开发小分子线粒体解偶联剂用于治疗非霍奇金淋巴瘤 酒精性脂肪性肝炎(NASH)，非酒精性脂肪性肝病(NAFLD)的一种晚期形式。大致 2600万人(约占美国人口的6%-8%)受到NASH的影响，超过30%的NASH患者- 相关的肝硬变将死于肝功能衰竭或肝细胞癌。目前还没有FDA批准的药物 治疗NASH和临床试验中的顶级药物遭遇无效或有不良副作用。纳什 以肝脏脂肪堆积、炎症和组织重塑为特征。线粒体解偶联 具有作为NASH疗法的强大潜力，因为它们针对脂肪堆积和 氧化应激。线粒体解偶联分子将质子从线粒体膜间间隙输送到 这种基质绕过了三磷酸腺苷合成酶。这一过程增加了脂肪的氧化，减少了线粒体的反应。 氧物种的产生；因此，直接靶向作为纳什病理生理基础的两条途径 推动炎症和纤维化反应。我们的实验室最近发现了线粒体- 具有广泛治疗窗口的选择性、安全性和口服生物利用型线粒体解偶联剂。证明- NASH加速小鼠模型(STAM模型)的原理研究达到了FDA的基准 NASH疗法的批准，将NAFLD活动评分(NAS)降低2分，至少1分 来自两个不同的NAS标准的积分，并且没有恶化的纤维化。这些强劲的初步数据 支持一项药物化学计划，以改善分子的类药物特性(目标1)并验证 与胰淀素饮食有关的更具生理和临床相关性的NASH小鼠模型中的分子(目标2)。 我们计划的主要创新是发现了具有不同水平的化学支架 线粒体解偶联能力是安全的和自我限制的。因为目前没有一种药物含有 线粒体解偶联作为临床上的主要作用模式，我们的计划可能是第一个提供 治疗NASH的线粒体解偶联剂。事实上，这个项目解决了一个关键的需求，并将使 对支持调节线粒体解偶联的安全性和有效性的数据有重大贡献 NASH的有效治疗。