Selective Targeting Agents for Mitochondria

• US 20140107317A1
• Filed: 10/21/2013
• Published: 04/17/2014
• Est. Priority Date: 01/06/2006
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Wipf, Peter, Xiao, Jingbo, Fink, Mitchell P., Kagan, Valerian E., Tyurina, Yulia Y., Kanai, Anthony J.
• Granted Patent: US 9,006,186 B2
• Time in Patent Office: Days
• US Class Current: 530/330
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/7034 attached to a carbocyclic compound, e.g. phloridzin
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: C07K 5/08 Tripeptides
• CPC Class Codes: C07K 5/10 Tetrapeptides
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

The present invention provides a composition and related methods for delivering cargo to a mitochondria which includes (a) a membrane active peptidyl fragment having a high affinity with the mitochondria and (b) cargo. The cargo may be selected from a wide variety of desired cargoes which are to be delivered to the mitochondria for a specific purpose. Compositions and methods are disclosed for treating an illness that is caused or associated with cellular damage or dysfunction which is caused by excessive mitochondrial production of reaction oxygen species (ROS). Compositions which act as mitochondria-selective targeting agents using the structural signaling of the β-turn recognizable by cells as mitochondria) targeting sequences are discussed. Mitochondria and cell death by way of apoptosis is inhibited as a result of the ROS-scavenging activity, thereby increasing the survival rate of the patient.

Claims

1. A compound having the structure:

2. The compound of claim 1 having the structure:

3. The compound of claim 1 having the structure:

4. The compound of claim 1 having the structure:

5. The compound of claim 1 in which R1 is a reactive oxygen species (ROS) scavenger.

6. The compound of claim 5 in which the ROS scavenger comprises a nitroxide radical.

7. The compound of claim 1 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).

8. The compound of claim 1, having the structure:

9. The compound of claim 8, having the structure:

10. The compound of claim 8 having the structure:

11. The compound of claim 8 having the structure:

12. The compound of claim 8 in which R1 is a reactive oxygen species (ROS) scavenger.

13. The compound of claim 12 in which the ROS scavenger comprises a nitroxide radical.

14. The compound of claim 8 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).

15. A method for delivering a cargo to mitochondria comprising contacting the mitochondria with a compound having the structure:

16. The method of claim 15, the compound having the structure:

17. The method of claim 15, the compound having the structure:

18. The method of claim 15, the compound having the structure:

19. The method of claim 15 in which R1 is a reactive oxygen species (ROS) scavenger.

20. The method of claim 18 in which the ROS scavenger comprises a nitroxide radical.

21. The method of claim 15 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).

22. The method of claim 15, the compound having the structure:

23. The method of claim 22, the compound having the structure:

24. The method of claim 22, the compound having the structure:

25. The method of claim 22, the compound having the structure:

26. The method of claim 22 in which R1 is a reactive oxygen species (ROS) scavenger.

27. The method of claim 26 in which the ROS scavenger comprises a nitroxide radical.

28. The method of claim 22 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).