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.

项目摘要酒精使用障碍（AUD）代表了一个主要的健康问题，该问题会导致大量死亡和全球残疾，强调了发展新型治疗策略的关键医疗需求。 GAO实验室最近显示，肝细胞特异性ALDH2缺陷小鼠（Aldh2Hep - / - ）对酒精 - 寻求血液乙醛水平升高的行为。有趣的是，aldh2hep - / - 鼠标也少得多与全球ALDH2敲除小鼠相比，能量消耗和运动能力降低。这些数据强调了肝脏 - 对ALDH2的特定抑制是一种有希望的治疗方法，用于治疗较少不需要的副作用。另外，肝细胞特异性有机阴离子运输多肽1（OATP1）转运蛋白（例如OATP1B1和OATP1B3）代表用于肝靶向药物的主要摄取转运蛋白类发展。我们的初步研究表明，小分子YA7068抑制了 ALDH2具有出色的效力（IC50 = 62 nm）。同时，YA7068充当OATP1B1的基板，导致ALDH2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ALDH2的酶活性来代谢是一种新型治疗策略音频。我们的目标是合成一系列YA7068类似物，并在体外既定测定法进行测试在体内，以验证和表征有效和肝脏特异性ALDH2抑制剂在治疗AUDS中。实现我们的目标，我们将合成使用新型计算机辅助药物设计的新的YA7068类似物设计（CADD）方法学SILCS（AIM 1）。合成的化合物将进行高通量 ALDH2酶试验确定其ALDH2的效力。选定的抑制剂将进一步评估它们对ALDH2对其他相关ALDH同工酶的特异性。新化合物的肝特异性摄取通过使用或没有表达的细胞内抑制剂水平，通过OATP1转运蛋白进行量化细胞表面上的OATP1转运蛋白。测试化合物的细胞内浓度将是其次是LC-MS。化合物的细胞毒性将使用原代人肝细胞进行测试。目标 2，我们将确定从AIM 1选择的顶部化合物的药代动力学和毒性。化合物，随后将在AUD鼠标模型中测试体内功效（请参阅Bin Gao博士的信）。我们的协作研究团队在执行CADD，铅优化以及体外和IN的良好记录化合物的体内评估。总的来说，我们的方法使我们处于识别，验证和表征ALDH2的第一类肝特异性抑制剂，并确定这种新型机制是否动作是开发AUD处理的可行选择。