Compositions and methods for cytoprotection
View Patent ↗The present invention provides compositions and methods for cytoprotection. In particular, it provides zinc chelate compositions comprising at least one zinc ion and at least one aminothiol ligand.
1. A method for protecting a mammalian cell from a cellular injury, the method comprising contacting the cell with a zinc chelate such that the cell has less damage than a comparable cell not contacted with the zinc chelate, wherein the cellular injury is chosen from chemical injury, thermal injury, ischemia-reperfusion injury, and mechanical trauma, and the zinc chelate comprises at least one zinc ion and at least one ligand selected from the group consisting of a compound comprising Formula (I), a compound comprising Formula (II), captopril, and 3,5-diisopropylsalicylic acid, the compounds comprising Formulas (I) or (II) having the following structures:
wherein:
R 1 is selected from the group consisting of hydrogen and acyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylamino, carboxyl, carboxylate ester, and carboxamide;
R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, carboxyl, carboxylate ester, and carboxamide, or together R 4 and R 5 form ═O;
R 6 is selected from the group consisting of hydrogen, alkyl, and acyl;
R 1′ and R 2′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and alkenyl, or together R 1′ and R 2′ form ═O; and
R 3′ and R 4′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, and (CHOH) n CH 2 OH, or together R 3′ and R 4′ form ═O, wherein n is an integer from 1 to 4.
2. The method of claim 1 , wherein the compound comprising Formula (I) is selected from the group consisting of N-acetylcysteine, cysteamine, cysteine, N-(2-mercaptopropionyl)glycine, and penicillamine, and the compound comprising Formula (II) is selected from the group consisting of 2-oxothiazolidine-4-carboxylic acid, 2-n-propylthiazolidine-4-carboxylic acid, 2-(1-ribosyl)thiazolidine-4-carboxylic acid, and thiazolidine-4-carboxylic acid.
3. The method of claim 1 , wherein the contacting between the cell and the zinc chelate occurs before the cellular injury.
4. The method of claim 1 , wherein the contacting between the cell and the zinc chelate occurs after the cellular injury.
5. The method of claim 1 , wherein the cell is within a subject selected from the group consisting of a primate, a companion animal, a zoo animal, and an agricultural animal.
6. The method of claim 1 , wherein the cell is within a human.
7. A method for protecting a mammalian cell from a radiation injury, the method comprising contacting the cell with a zinc chelate such that the cell has less damage than a comparable cell not contacted with the zinc chelate, wherein the zinc chelate comprises at least one zinc ion and at least one aminothiol ligand selected from the group consisting N-acetylcysteine, captopril, penicillamine, and a compound comprising Formula (II):
wherein:
R 1′ and R 2′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and alkenyl, or together R 1′ and R 2′ form ═O; and
R 3′ and R 4′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, and (CHOH) n CH 2 OH, or together R 3′ and R 4′ form ═O, wherein n is an integer from 1 to 4.
8. The method of claim 7 , wherein the radiation is selected from the group consisting of gamma radiation, beta radiation, X-ray radiation, and ultraviolet radiation.
9. The method of claim 7 , wherein the compound comprising Formula (II) is selected from the group consisting of 2-(1-ribosyl)thiazolidine-4-carboxylic acid, 2-n-propylthiazolidine-4-carboxylic acid, 2-oxothiazolidine-4-carboxylic acid, and thiazolidine-4-carboxylic acid.
10. The method of claim 7 , wherein the zinc chelate is contacted with the cell before the cell is subjected to the radiation.
11. The method of claim 7 , wherein the zinc chelate is contacted with the cell after the cell is subjected to the radiation.
12. The method of claim 7 , wherein the cell is within a subject selected from the group consisting of a primate, a companion animal, a zoo animal, and an agricultural animal.
13. The method of claim 7 , wherein the cell is within a human.
14. The method of claim 12 , wherein the zinc chelate is administered to the subject in a route selected from the group consisting of oral, inhalation, transdermal, transmucosal, intravenous, intramuscular, and subcutaneous.
15. The method of claim 12 , wherein the zinc chelate is administered to the subject in an oral dosage form.
16. The method of claim 14 , wherein the zinc aminothiol zinc chelate is administered to the subject from about 0.5 hour to about 1 hour before exposure to the radiation at a dose of about 0.01 to about 2.5 grams, and administered to the subject every four to six hours after the radiation at a dose of about 0.01 to about 2 grams for about seven days.
17. The method of claim 14 , wherein the zinc chelate is administered to the subject from about 0.5 hour to about 1 hour before exposure to the radiation at a dose of about 0.5 grams, and administered to the subject every four to six hours after the radiation at a dose of about 0.25 grams for about seven days.
18. The method of claim 14 , wherein the zinc chelate is administered to the subject every four to six hours after the radiation at a dose of about 0.01 to about 2 grams for about seven days.
19. The method of claim 14 , wherein the zinc chelate is administered to the subject every four to six hours after the radiation at a dose of about 0.25 grams for about seven days.
20. The method of claim 15 , wherein the zinc chelate is coadministered with an agent selected from the group consisting of a buffering agent, a proton pump inhibitor, and a histamine H2 blocker.
21. The method of claim 7 , wherein the zinc chelate is zinc-2-(1-ribosyl)thiazolidine-4-carboxylic acid (Zn-RibCys).
22. The method of claim 1 , wherein the zinc chelate is zinc-2-(1-ribosyl)thiazolidine-4-carboxylic acid (Zn-RibCys).
23. The method of claim 7 , wherein the zinc chelate is selected from the group consisting of zinc-N-acetylcysteine (Zn-NAC), zinc-penicillamine (Zn-penicillamine), zinc-captopril (Zn-captopril), zinc-2-(1-ribosyl)thiazolidine-4-carboxylic acid (Zn-RibCys), and zinc-thiazolidine-4-carboxylic acid (Zn-PTCA).