Neuroprotective chemicals and methods for identifying and using same

Patent metadata

Field	Value
Publication number	US-9243281-B2
Application number	US-201414540006-A
Country	US
Kind code	B2
Filing date	Nov 12, 2014
Priority date	Nov 11, 2013
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

Provided herein are methods for identifying a compound having cell-protective (e.g., neuroprotective) activity. Compounds identified therefrom are also provided. These compounds can be used to treat various diseases, disorders, or conditions associated with, for example, unwanted cell death.

First claim

The invention claimed is:

1. A method for identifying a compound having cell-protective activity, comprising:
exposing a population of cells to a test compound and a DNA-damaging agent;
determining survival rate of the population of cells;
wherein an increase in the survival rate compared to a control that is not treated with the test compound is indicative of cell-protective activity of the test compound; and
incubating the test compound with nicotinamide phosphoribosyltransferase (NAMPT) and measuring an activity of the NAMPT, wherein an increase in the activity of the NAMPT additionally confirms the cell-protective activity of the test compound.

2. The method of claim 1 , wherein the exposing step comprises incubating the population of cells with the test compound and the DNA-damaging agent.

3. The method of claim 1 , wherein the exposing step comprises incubating the population of cells with the test compound first, followed by the DNA-damaging agent.

4. The method of claim 1 , wherein the exposing step comprises incubating the population of cells with the DNA-damaging agent first, followed by the test compound.

5. The method of claim 1 , wherein the DNA-damaging agent activates poly-ADP-ribose polymerase (PARP).

6. The method of claim 5 , wherein the DNA-damaging agent leads to decline in nicotinamide adenine dinucleotide (NAD) level.

7. The method of claim 1 , wherein the DNA-damaging agent is an anthracycline.

8. The method of claim 7 , wherein the anthracycline is one or more of daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin and mitoxantrone.

9. The method of claim 8 , wherein the anthracycline is doxorubicin.

10. The method of claim 1 , wherein the cells are mammalian cells.

11. The method of claim 1 , wherein the test compound is provided at about 1-20 uM, or about 2-10 uM or about 5 uM.

12. The method of claim 1 , wherein the test compound is a small molecule.

13. The method of claim 1 , wherein the DNA-damaging agent is provided at about 0.01-20 uM, or about 0.05-10 uM, or about 0.1-1.5 uM, or about 0.5 uM.

14. The method of claim 1 , further comprising determining the test compound having said cell-protective activity protects the cells from toxicity mediated by the DNA-damaging agent.

15. The method of claim 1 , further comprising determining the test compound having said cell-protective activity does not protect the cells from toxicity induced by a toxin selected from the group consisting of bortezomib, staurosporine, taxol, brefeldin, cytochalasin D, TNFa and TRAIL.

16. The method of claim 12 , further comprising determining the test compound having said cell-protective activity increases nicotinamide adenine dinucleotide (NAD) level.

17. The method of claim 1 , further comprising determining the test compound having said cell-protective activity binds and/or activates the NAMPT.

18. The method of claim 1 , wherein the cell-protective activity is neuroprotective activity which includes one or more of: promoting survival, health, integrity, growth, development and/or function of neurons, protecting neurons from cell death, apoptosis and/or degeneration, and stimulating neurogenesis.

Assignees

• Univ Texas

Inventors

• Mcknight Steven L
• Ready Joseph M
• Pieper Andrew A
• Wang Gelin
• Han Ting

Classifications

• G01N33/5038

  involving detection of metabolites per se · CPC title

• G01N33/5014 Primary

  for testing toxicity · CPC title

• C12Q1/48 Primary

  involving transferase · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• G01N2333/91142

  Pentosyltransferases (2.4.2) · CPC title