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Principal Investigator: Fengtian Xue
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2024
Award: $183,469
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <1,2-Benzo-Pyrones><1,2-Benzopyrones><1,2-benzopyrone><ALDH><Absolute ethanol><Acetaldehyde><Acetates><Active Sites><Address><Alcohol Drinking><Alcohol consumption><Alcohol dehydrogenase><Alcohol dependence><Alcohol-NAD+ Oxidoreductase><Alcoholic Cirrhosis><Alcoholic Hepatic Cirrhosis><Alcoholic Liver Cirrhosis><Alleles><Allelomorphs><Antabuse><Asian ancestry><Asian descent><Assay><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Cardiac><Cell Body><Cell surface><Cells><Cephalalgia><Cephalgia><Cephalodynia><Cessation of life><Clinical><Computer Assisted><Computer-Aided Design><Computer-Assisted Design><Coumarines><Coumarins><Coupling><Cranial Pain><Dangerousness><Data><Death><Development><Disulfiram><Drug Design><Drug Kinetics><Drug Targeting><ETOH><East Asian><Energy Expenditure><Energy Metabolism><Enzyme Gene><Enzymes><EtOH drinking><EtOH use><Ethanal><Ethanol><Ethyl Alcohol><Face><Family><Feeling><Flushing><Gene Deletion><Goals><Grain Alcohol><Half-Life><Head Pain><Headache><Health><Heavy Drinking><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Human Figure><Human body><Hypotension><In Vitro><In vivo analysis><Individual><Intermediary Metabolism><Isoenzymes><Isozymes><KO mice><Knock-out Mice><Knockout Mice><Letters><Ligands><Liver><Liver Cells><Low Blood Pressure><Maps><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medical><Metabolic Clearance Rate><Metabolic Processes><Metabolism><Methodology><Methods><Methylcarbinol><Mice><Mice Mammals><Mitochondria><Modern Man><Motility><Murine><Mus><NIAAA><National Institute on Alcohol Abuse and Alcoholism><Nausea><Null Mouse><OATP Proteins><OATP Transporters><Organic Anion Transport Polypeptides><Palpitations><Persons><Pharmacokinetics><Population><Portal Cirrhosis><Position><Positioning Attribute><Preventative strategy><Prevention strategy><Preventive strategy><Reaction><Reporting><Research><Research Priority><Resistance><Risk><Role><Series><Site><Specificity><Spottings><Structure><Structure-Activity Relationship><Surface><Tachycardia><Testing><Tetraethylthiuram Disulfide><Therapeutic><Tonka Bean Camphor><Toxic effect><Toxicities><Vascular Hypotensive Disorder><alcohol abuse therapy><alcohol abuse treatment><alcohol addiction><alcohol dependency><alcohol dependent><alcohol ingestion><alcohol intake><alcohol product use><alcohol seeking><alcohol seeking behavior><alcohol treatment><alcohol use><alcohol use disorder><alcohol use prevention><alcoholic beverage consumption><alcoholic drink intake><aldehyde dehydrogenases><alpha benzopyrone><analog><chemical structure function><clearance rate><computer aided><coumarin><design><designing><deter alcohol use><developmental><disability><disease model><disorder model><drink heavily><drinking><drug development><effective therapy><effective treatment><end-stage organ failure><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol seeking><ethanol use><ethanol use disorder><ethanol-seeking behavior><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><extreme drinking><faces><facial><feelings><gene deletion mutation><head ache><heavy alcohol use><hepatic body system><hepatic organ system><in vitro Assay><in vivo><in vivo evaluation><in vivo testing><inhibitor><lead optimization><liver function><mitochondrial><mouse model><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pharmacologic><prevent alcohol use><resistant><shRNA><short hairpin RNA><side effect><small hairpin RNA><small molecule><social role><structure function relationship><treatment strategy><uptake><virtual screening><virtual screenings>