ALDH2 inhibitors for the treatment of AUD

ALDH2抑制剂用于治疗AUD

基本信息

批准号：
10664502
负责人：
Fengtian Xue
金额：
$ 22.21万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2023-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664502
关键词：
Acetaldehyde Acetates Active Sites Address Alcohol consumption Alcohol dehydrogenase Alcohol dependence Alcoholic Liver Cirrhosis Alleles Asian ancestry Biological Assay Blood Cardiac Cell surface Cells Cessation of life Clinical Computer Assisted Computer-Aided Design Coumarins Coupling Dangerousness Data Development Disease model Disulfiram Drug Design Drug Kinetics Drug Targeting East Asian Energy Metabolism Enzymes Ethanol Face Family Feeling Flushing Gene Deletion Goals Half-Life Headache Health Heavy Drinking Hepatocyte Human Human body Hypotension In Vitro Individual Isoenzymes Knockout Mice Letters Ligands Liver Maps Maximum Tolerated Dose Medical Metabolic Clearance Rate Metabolism Methodology Methods Mitochondria Mus National Institute on Alcohol Abuse and Alcoholism Nausea OATP Transporters Palpitations Persons Population Positioning Attribute Prevention strategy Reaction Reporting Research Research Priority Resistance Risk Role Series Site Specificity Spottings Structure Structure-Activity Relationship Surface Tachycardia Testing Therapeutic Toxic effect alcohol abuse therapy alcohol seeking behavior alcohol use disorder aldehyde dehydrogenases analog cell motility design deter alcohol use disability drinking drug development effective therapy end-stage organ failure in vitro Assay in vivo in vivo evaluation inhibitor lead optimization liver function mouse model novel novel therapeutic intervention pharmacologic side effect small hairpin RNA small molecule treatment strategy uptake virtual screening

项目摘要

PROJECT SUMMARY Alcohol use disorders (AUDs) represent a leading health issue that causes an enormous number of deaths and disabilities globally, highlighting the critical medical need for the development of novel therapeutic strategies. The Gao Lab recently showed that hepatocyte-specific Aldh2-deficient mice (Aldh2hep-/-) were resistant to alcohol- seeking behavior with elevated blood acetaldehyde levels. Interestingly, Aldh2hep-/- mice also had much less reduced energy expenditure and motility than the global Aldh2 knockout mice. These data highlight that liver- specific inhibition of ALDH2 represents a promising therapeutic approach for the treatment of AUDs with fewer unwanted side effects. In addition, the hepatocyte-specific organic anion transporting polypeptide 1 (OATP1) transporters (eg, OATP1B1 and OATP1B3) represent a major class of uptake transporters for liver-targeted drug development. Our preliminary studies have shown that small-molecule YA7068 inhibits the enzymatic activity of ALDH2 with an excellent potency (IC50 = 62 nM). Simultaneously, YA7068 functions as a substrate for OATP1B1, leading to liver-specific targeting of ALDH2. Our hypothesis is that liver-specific inhibition of acetaldehyde metabolism by targeting the enzymatic activity of ALDH2 is a novel therapeutic strategy for the treatment of AUDs. Our goal is to synthesize a series of YA7068 analogs and test them using established assays in vitro and in vivo, to validate and characterize potent and liver specific ALDH2 inhibitors in treating AUDs. To achieve our goal, we will synthesize new YA7068 analogs that have been designed using a novel computer-aided drug design (CADD) methodology SILCS (Aim 1). The synthesized compounds will be subjected to a high-throughput ALDH2 enzymatic assay to determine their potencies for ALDH2. Selected inhibitors will be further assessed for their specificity for ALDH2 against other related ALDH isozymes. The liver-specific uptake of new compounds by OATP1 transporters will be quantified by comparing intracellular inhibitor levels with or without the expression of the OATP1 transporters on the cell surface. The intracellular concentration of testing compounds will be followed by LC-MS. The cellular toxicity of compounds will be tested using primary human hepatocytes. In Aim 2, we will determine the pharmacokinetics and toxicity of the top compound selected from Aim 1. For the top compound, in vivo efficacy will subsequently be tested in AUD mouse models (see letter from Dr. Bin Gao). Our collaborative research team has a strong track record of performing CADD, lead optimization, and in vitro and in vivo evaluation of compounds. Collectively, our approach puts us in a unique position to identify, validate, and characterize first-in-class liver-specific inhibitors of ALDH2, and to determine whether this novel mechanism of action is a viable option for the development of a treatment for AUDs.

项目概要酒精使用障碍 (AUD) 是导致大量死亡和死亡的主要健康问题全球范围内的残疾问题，凸显了开发新型治疗策略的迫切医疗需求。高实验室最近表明，肝细胞特异性 Aldh2 缺陷小鼠 (Aldh2hep-/-) 对酒精具有抵抗力寻求血液乙醛水平升高的行为。有趣的是，Aldh2hep-/- 小鼠也少得多与全球 Aldh2 敲除小鼠相比，能量消耗和运动能力降低。这些数据强调肝脏 ALDH2 的特异性抑制代表了一种有前途的治疗 AUD 的方法，且花费较少不需要的副作用。此外，肝细胞特异性有机阴离子转运多肽 1 (OATP1) 转运蛋白（例如，OATP1B1 和 OATP1B3）代表肝脏靶向药物的一类主要摄取转运蛋白发展。我们的初步研究表明，小分子 YA7068 抑制酶活性 ALDH2 具有出色的效力 (IC50 = 62 nM)。同时，YA7068 作为 OATP1B1 的底物，导致 ALDH2 的肝脏特异性靶向。我们的假设是乙醛的肝脏特异性抑制通过靶向 ALDH2 酶活性进行代谢是治疗以下疾病的一种新治疗策略澳元。我们的目标是合成一系列 YA7068 类似物，并使用已建立的体外测定法对其进行测试体内，验证和表征有效的肝脏特异性 ALDH2 抑制剂治疗 AUD 的效果。为了实现我们的我们的目标是合成新的 YA7068 类似物，这些类似物是使用新型计算机辅助药物设计的设计 (CADD) 方法 SILCS（目标 1）。合成的化合物将进行高通量 ALDH2 酶测定以确定其对 ALDH2 的效力。选定的抑制剂将被进一步评估它们对 ALDH2 与其他相关 ALDH 同工酶的特异性。新化合物的肝脏特异性摄取通过比较有或没有表达的细胞内抑制剂水平来量化 OATP1 转运蛋白细胞表面的 OATP1 转运蛋白。测试化合物的细胞内浓度为随后进行 LC-MS。将使用原代人肝细胞测试化合物的细胞毒性。瞄准 2，我们将确定从目标1中选择的顶级化合物的药代动力学和毒性。化合物的体内功效随后将在 AUD 小鼠模型中进行测试（参见高斌博士的来信）。我们的合作研究团队在执行 CADD、先导化合物优化以及体外和体内方面拥有良好的记录。化合物的体内评价。总的来说，我们的方法使我们处于独特的地位来识别、验证和表征一流的 ALDH2 肝脏特异性抑制剂，并确定这种新机制是否行动是开发 AUD 治疗方法的可行选择。