ALDH2 inhibitors for the treatment of AUD

ALDH2抑制剂用于治疗AUD

• 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
• 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

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.

项目摘要 酒精使用障碍（AUD）是一个主要的健康问题，导致大量死亡， 全球残疾人问题，突出了开发新的治疗策略的关键医疗需求。 Gao实验室最近表明，肝细胞特异性Aldh 2缺陷小鼠（Aldh 2 hep-/-）对酒精具有抗性， 血液乙醛水平升高的行为。有趣的是，Aldh 2 hep-/-小鼠也有少得多的 降低的能量消耗和运动性比全球Aldh 2敲除小鼠。这些数据表明，肝脏- 特异性抑制ALDH 2代表了一种有前途的治疗AUD的治疗方法， 副作用此外，肝细胞特异性有机阴离子转运多肽1（OATP 1） 转运蛋白（例如，OATP 1B 1和OATP 1B 3）代表肝靶向药物的主要一类摄取转运蛋白 发展我们的初步研究表明，小分子YA 7068抑制了 ALDH 2具有优异的效力（IC 50 = 62 nM）。同时，YA 7068作为OATP 1B 1的底物， 导致ALDH 2的肝特异性靶向。我们的假设是肝脏特异性抑制乙醛 通过靶向ALDH 2的酶活性来抑制ALDH 2的代谢是一种用于治疗ALDH 2的新的治疗策略。 AUD。我们的目标是合成一系列YA 7068类似物，并使用已建立的体外试验对其进行测试， 在体内，验证和表征有效的和肝特异性的ALDH 2抑制剂在治疗AUD中的作用。实现我们 目标是，我们将合成使用新型计算机辅助药物设计的新YA 7068类似物 设计（CADD）方法SILCS（目标1）。合成的化合物将进行高通量的 ALDH 2酶测定以确定它们对ALDH 2的效力。将进一步评估选定的抑制剂， 它们对ALDH 2的特异性与其它相关的ALDH同工酶有关。新化合物的肝脏特异性摄取 将通过比较有或没有表达的细胞内抑制剂水平来定量OATP 1转运蛋白 OATP 1转运蛋白的表达。测试化合物的细胞内浓度将是 将使用原代人肝细胞测试化合物的细胞毒性。在Aim中 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。中国最高 对于化合物，随后将在AUD小鼠模型中测试体内功效（参见来自Dr Bin Gao的信件）。我们 协作研究团队在执行CADD、先导化合物优化以及体外和体内研究方面有着良好的记录 化合物的体内评价。总的来说，我们的方法使我们处于一个独特的位置，以确定，验证， 表征一流的ALDH 2肝脏特异性抑制剂，并确定这种新的机制是否 行动是开发AUD治疗的可行选择。