Therapeutic Mitochondrial Uncouplers

治疗性线粒体解偶联剂

基本信息

批准号：
10608112
负责人：
Webster L Santos
金额：
$ 54.24万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
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/10608112
关键词：
2,4-Dinitrophenol Acceleration Address Affect Animal Model Benchmarking Biological Assay Biological Availability 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 Liver Failure Liver diseases Mediating Mitochondria Mitochondrial Matrix Modeling Mus Nature Oral Oxidative Stress Pathology Pathway interactions Patients Persons 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 Rodent Model Safety Source Specificity Streptozocin Structure-Activity Relationship Testing Therapeutic Therapeutic Effect Tissues Toxic effect clinically relevant design drug-like compound efficacious treatment efficacy validation fatty liver disease hepatocyte injury improved in vivo in vivo evaluation innovation islet amyloid polypeptide 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

项目摘要

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.

项目概要该项目的目标是开发小分子线粒体解偶联剂，用于治疗非酒精性脂肪性肝炎（NASH），非酒精性脂肪肝病（NAFLD）的一种晚期形式。大约 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- 相关的肝硬化会死于肝功能衰竭或肝细胞癌。目前尚无 FDA 批准的药物治疗 NASH 的顶级药物在临床试验中要么无效，要么有不良副作用。非酒精性脂肪性肝炎其特点是肝脏中脂肪堆积、炎症和组织重塑。线粒体解偶联剂由于其针对脂肪积累的作用模式的性质，具有作为 NASH 疗法的强大潜力，并且氧化应激。线粒体解偶联剂将质子从线粒体膜间隙转运到基质绕过 ATP 合酶。这个过程增加脂肪氧化并降低线粒体反应性氧气的产生；因此，直接针对 NASH 病理生理学基础的两条途径驱动炎症和纤维化反应。我们的实验室最近发现了线粒体—— 选择性、安全且口服生物可利用的线粒体解偶联剂，具有广泛的治疗窗口。证明- NASH 加速小鼠模型（STAM 模型）的原理研究达到了 FDA 基准通过将 NAFLD 活动评分 (NAS) 降低 2 分来批准 NASH 治疗方法，其中至少有一项点来自两种不同的 NAS 标准，并且纤维化没有恶化。这些强有力的初步数据支持药物化学计划，以改善分子的类药特性（目标 1）并验证在涉及 Amylin 饮食的 NASH 小鼠模型中进行更生理和临床相关的分子研究（目标 2）。我们项目的主要创新是发现具有不同水平的新型化学支架安全且具有自限性的线粒体解偶联能力。由于目前尚无药物具有线粒体解偶联作为临床的主要作用模式，我们的计划可能是第一个提供线粒体解偶联剂用于治疗 NASH。事实上，该项目解决了一个关键需求，并将使对支持调节线粒体解偶联的有效性的数据做出了重大贡献，以实现安全和有效治疗 NASH。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.

同时针对饮食诱导的肥胖小鼠的卡路里摄入量和卡路里效率的有益效果。

DOI：
10.1042/cs20231016
发表时间：
2024
期刊：
Clinical science (London, England : 1979)
影响因子：
0
作者：
Chen,Sing-Young;Telfser,AidenJ;Olzomer,EllenM;Vancuylenberg,CalumS;Zhou,Mingyan;Beretta,Martina;Li,Catherine;Alexopoulos,StephanieJ;Turner,Nigel;Byrne,FrancesL;Santos,WebsterL;Hoehn,KyleL
通讯作者：
Hoehn,KyleL