Methods for decreasing set in inhibiting protein phosphatase 2A (PP2A) and/or increasing the activity of cyclin-dependent kinase 5 (CDK5) by an APOE peptide

• US 9,730,979 B2
• Filed: 12/21/2007
• Issued: 08/15/2017
• Est. Priority Date: 12/21/2006
• Status: Active Grant

• Current Assignee: Cornerstone Biosciences, Inc.
• Original Assignee: Cognosci, Inc.
• Inventors: Vitek, Michael P., Christensen, Dale J., Oddo, Jessica
• Primary Examiner(s): WANG, CHANG YU
• Application Number:
  US12/519,278
• Publication Number:
  US 20100144627A1
• Time in Patent Office: 3,525 Days
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/775 : Apolipopeptides

Abstract

The present invention provides methods for modulating SET activity by contacting SET with a binding agent such as an ApoE peptide derivative. In one embodiment of the invention, a pharmaceutical composition capable of modulating SET activity is administered to a patient for the treatment of an inflammatory or neurological condition. In another embodiment of the invention, compounds efficacious for the treatment of inflammatory and neurological conditions are identified by screening for a binding agent capable of competing with or inhibiting the binding of an ApoE derivative to SET.

Claims

1. A method of decreasing an activity of SET comprising contacting SET with an ApoE peptide, wherein the activity of SET is inhibition of Protein Phosphatase 2A (PP2A) and/or increasing the activity of Cyclin-Dependent Kinase 5 (CDK5), and wherein the ApoE peptide is capable of binding to SET and consists of the amino acid sequence of SEQ ID NO:

1 or SEQ ID NO;

2, and wherein the activity of SET is decreased upon contact with the ApoE peptide.

2. The method of claim 1, wherein said peptide consists of the amino acid sequence of SEQ ID NO:

1.

3. The method of claim 1, wherein said peptide consists of the amino acid sequence of SEQ ID NO:

2.

4. The method of claim 1, wherein administration of the ApoE peptide reduces phosphorylated p38 Mitogen Activated Protein (MAP) kinase.

5. The method of claim 1, wherein administration of the ApoE peptide reduces LPS-induced nitric oxide.

6. The method of claim 1, wherein administration of the ApoE peptide increases phosphatase activity of PP2A.

7. The method of claim 1, wherein administration of the ApoE peptide reduces Jcasp-induced cell death.

8. The method of claim 1, wherein administration of the ApoE peptide reduces kinase activity of CDK5.

9. A method of identifying an agent that binds to SET and decreases SET activity, comprising contacting SET with at least one test agent to identify one or more agents that bind to SET, and screening said one or more agents for the ability to compete with or inhibit binding of a peptide consisting of the amino acid sequence of SEQ ID NO:

1 to SET, wherein the activity of SET is inhibition of Protein Phosphatase 2A (PP2A) and/or increasing the activity of Cyclin-Dependent Kinase 5 (CDK5).

10. The method of claim 9, further comprising isolating one or more agents that compete with or inhibit binding of a peptide consisting of the amino acid sequence of SEQ ID NO:

1 to SET.

11. The method of claim 10, further comprising

screening said one or more agents for the ability to increase phosphatase activity of PP2A.

12. The method of claim 10, further comprising screening said one or more agents for the ability to decrease kinase activity of CDK5.