Compounds and Methods for Treatment of Alpha-1 Antitrypsin Deficiency
AssigneeUniversity of Florida Research Foundation, Inc.
InventorsChen Liu, David A. Ostrov
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Abstract
The invention features compositions and methods that are useful for treating or preventing AAT deficiency and associated conditions. In addition, the invention provides methods for identifying compounds useful for treatment of AAT deficiency and associated conditions.
Claims23
A method of treating alpha-1 antitrypsin (AAT) deficiency in a subject in need of such treatment, the method comprising administering to the subject a compound capable of disrupting polymerization of the mutant Z form of AAT under conditions such that AAT deficiency is treated.
A method of reducing the accumulation of the mutant Z form of alpha-1 antitrypsin (AAT) in a cell or increasing the secretion of alpha-1 antitrypsin (AAT) from a cell producing a mutant Z form of AAT, or inhibiting the polymerization of the mutant Z form of alpha-1 antitrypsin (AAT) in a cell, the method comprising contacting the cell with a compound capable of disrupting polymerization of the mutant Z form of AAT under conditions such that accumulation of the mutant Z form of alpha-1 antitrypsin in the cell is reduced.
(canceled)
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8-13. (canceled)
A kit for the treatment of AAT deficiency, the kit comprising
- an effective amount of the amount of a compound capable of disrupting polymerization of the mutant Z form of AAT;
- and
- instructions for administering the compound capable of disrupting polymerization of the mutant Z form of AAT to a subject to treat AAT deficiency.
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A method for evaluating the potential of a chemical entity to associate with a) a molecule or molecular complex comprising a binding pocket defined by structure coordinates of AAT protein monomer amino acid residues in the P6-P3 region of the AAT protein, or b) a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 2.0 (more preferably 1.5) angstroms,
- the method comprising the steps of:
- i) employing computational means to perform a fitting operation between the chemical entity and a binding pocket of the molecule or molecular complex;
- and
- ii) analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding pocket.
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A method of treating or preventing liver damage or preserving liver function in a subject suffering from alpha-1 antitrypsin (AAT) deficiency, the method comprising administering to the subject a compound capable of disrupting polymerization of the mutant Z form of AAT or a compound capable of increasing secretion of the mutant Z form of AAT from a hepatocyte under conditions such that liver damage in the subject is treated or prevented or liver function is preserved.
23-29. (canceled)
A method of treating or preventing lung damage or preserving lung function in a subject suffering from alpha-1 antitrypsin (AAT) deficiency, the method comprising administering to the subject a compound capable of disrupting polymerization of the mutant Z form of AAT or increasing the secretion of alpha-1 antitrypsin (AAT) from a cell producing a mutant Z form of AAT, under conditions such that lung damage in the subject is treated or prevented or lung function is preserved.
34-40. (canceled)
Dependencies are inferred from the claim text.