: The alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive genetic disorder causing both liver and lung diseases, for which there is no effective treatment. The prototype of AAT deficiency, PiZZ, affects one in 1,800 live births in Northern European and North American populations. The fundamental pathological process is that the accumulation of mutant AAT in the form of polymers within hepatocytes causes low levels of AAT in the serum, resulting in lung tissue damage by proteinases. The protein accumulation also causes liver disease. A potential approach to treat AAT deficiency is to prevent AAT polymer formation and facilitate the mutant protein secretion from the hepatocytes. The secretion of the protein may simultaneously alleviate both the liver disease and the lung disease. Biochemical analysis and crystal structural analysis have identified the site that is responsible for AAT polymerization. This site is an attractive target for therapeutic intervention. We hypothesize that specific small molecules that interfere with AAT polymerization can be identified by a molecular docking approach combined with functional testing in cell culture systems. We will test this hypothesis through two specific aims: 1. To identify potential lead compounds through in silico molecular docking program using the National Cancer Institute/Developmental Therapeutics Program (NCI/DTP) depository. 2. The lead compounds will be tested in two unique cell culture systems recently developed in our laboratory: mutant AAT expression stable hepatoma cell line and an immortalized human PiZZ liver cell line derived from a young child with AAT deficiency. This exploratory investigation will allow us to develop a novel approach toward target therapy for this genetic disease. Moreover, success in this study will validate this methodology for prospective identification of molecular therapies for deranged protein: protein interactions.
