Immunophilin Ligands and Methods for Modulating Immunophilin and Calcium Channel Activity
First Claim
Patent Images
1. A purified complex comprising an immunophilin ligand, and one or both of (i) an immunophilin or a functional fragment thereof and/or (ii) a calcium channel subunit or a functional fragment thereof.
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Abstract
Immunophilin ligands and their uses as modulators of calcium channel activity are disclosed. Screening, therapeutic and prophylactic methods for conditions associated with calcium channel dysfunction, e.g., neurodegenerative and cardiovascular disorders, are also disclosed.
26 Citations
59 Claims
- 1. A purified complex comprising an immunophilin ligand, and one or both of (i) an immunophilin or a functional fragment thereof and/or (ii) a calcium channel subunit or a functional fragment thereof.
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11. A recombinant host cell comprising a first recombinant nucleic acid that comprises a nucleotide sequence encoding an FKBP52 having the amino acid sequence shown in
FIGS. 12A-12D (SEQ ID NO:- 11-14, and/or a second recombinant nucleic acid that comprises a nucleotide sequence encoding a β
1 subunit of the voltage gated L-type calcium channel having the amino acid sequence shown inFIGS. 11A-11J (SEQ ID NO;
1-10).
- 11-14, and/or a second recombinant nucleic acid that comprises a nucleotide sequence encoding a β
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13. A method for identifying a test compound that increases the formation of a complex that includes the test compound, and one or both of (i) an immunophilin and/or (ii) a β
- 1 subunit of the voltage gated L-type calcium channel, comprising;
contacting an immunophilin or a functional fragment thereof, and/or a β
1 subunit or a functional fragment thereof, with a test compound under conditions that allow formation of the complex;detecting the presence of the complex in the presence of the test compound relative to a reference; wherein an increase in the level of the complex in the presence of the test compound, relative to the level of the complex in the reference, indicates that said test compound increases complex formation. - View Dependent Claims (14, 15, 16, 17, 18, 56, 59)
- 1 subunit of the voltage gated L-type calcium channel, comprising;
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19. A method of increasing the formation of a complex that includes an immunophilin ligand, and one or both of (i) an immunophilin or a functional variant thereof and/or (ii) a calcium channel subunit or a functional variant thereof, comprising:
- contacting an immunophilin or a functional fragment thereof, and/or a β
1 subunit of the voltage gated L-type calcium channel or a functional fragment thereof, with an immunophilin ligand, under conditions that increase formation of the complex. - View Dependent Claims (20)
- contacting an immunophilin or a functional fragment thereof, and/or a β
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21. A method of decreasing voltage-gated calcium channel activity, and/or FKBP52 activity, in a cell, comprising, contacting a cell that expresses one or both of an FKBP52 or a functional fragment thereof, and/or a β
- 1 subunit of the voltage gated L-type calcium channel or a functional fragment thereof, with an immunophilin ligand under conditions that allow binding between the immunophilin ligand, and one or both of the FKBP52 or fragment thereof, and/or the subunit or fragment thereof, to occur, thereby inhibiting the calcium channel activity.
- View Dependent Claims (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)
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33. A method of stimulating neurite outgrowth and/or survival of a neuronal cell, comprising, contacting the neuronal cell with an immunophilin ligand, wherein the immunophilin ligand is present at a concentration that elicits one or more of the following:
- (i) downregulates expression or activity at least one component of the calcium signaling pathways;
(ii) decreases FKBP52 activity or expression;
(iii) reduces or inhibits the activity or expression of an L-type calcium channel;
(iv) activates glucocorticoid receptor signaling;
(v) induces formation of a complex that comprises the immunophilin ligand, FKBP52 and/or a β
1 subunit; and
/or (vi) protects neurons from calcium-induced cell death. - View Dependent Claims (34, 35, 36, 44, 45, 46, 47)
- (i) downregulates expression or activity at least one component of the calcium signaling pathways;
- 37. A method of treating a disorder associated with L-type calcium channel dysfunction, comprising administering to a subject an immunophilin ligand in an amount sufficient to form a complex that includes the immunophilin ligand, and one or both of an immunophilin or a functional fragment thereof, and/or a calcium channel subunit or a functional fragment thereof, thereby treating the disorder.
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48. A method of stimulating neurite outgrowth of a neuronal cell, comprising contacting the neuronal cell with one or both of an antagonist of a β
- 1 subunit of a voltage gated L-type calcium channel, and/or an antagonist of FKBP52, under condition that reduce the activity or expression of the β
1 subunit or FKBP52. - View Dependent Claims (49, 50, 51, 52)
- 1 subunit of a voltage gated L-type calcium channel, and/or an antagonist of FKBP52, under condition that reduce the activity or expression of the β
- 53. Use of an immunophilin ligand in the manufacture of a medicament for the prophylaxis or treatment of a condition associated with L-type calcium channel dysfunction.
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55. Use of an immunophilin ligand in combination with an L-type calcium channel antagonist for the prophylaxis or treatment of a condition associated with L-type calcium channel dysfunction.
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57. An immunophilin ligand for use in the prophylaxis or treatment of a condition associated with L-type calcium channel dysfunction.
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58. A composition comprising an immunophilin ligand and an L-type calcium channel antagonist for use in the prophylaxis or treatment of a condition associated with L-type calcium channel dysfunction.
Specification