Selective targeting agents for mitochondria

• US 7,718,603 B1
• Filed: 12/01/2006
• Issued: 05/18/2010
• 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, Kanai, Anthony J., Fink, Mitchell P., Kagan, Valerian E., Tyurina, Yulia Y.
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): Bradley; Christina
• Application Number:
  US11/565,779
• Time in Patent Office: 1,264 Days
• Field of Search: None
• US Class Current: 514/1.2
• 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 cargos 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. In a preferred embodiment, the compositions and methods may be administered therapeutically in the field to patients with profound hemorrhagic shock so that survival could be prolonged until it is feasible to obtain surgical control of the bleeding vessels. In further preferred embodiments, the composition for scavenging radicals in a mitochondria membrane includes a radical scavenging agent and a membrane active compound having a high affinity with said mitochondrial membrane and associated methods. In another embodiment, the cargo transported by mitochondrial-selective targeting agents may include an inhibitor of nitric oxide synthase (NOS) enzyme activity.

Claims

1. A compound having the structure:

2. A compound having the structure:

3. A compound having the structure:

4. A compound having the structure:

5. A compound having the structure:

6. A compound having the structure:

7. A method for delivering 2-amino-6-methyl-thiazine to mitochondria comprising contacting the mitochondria with a compound selected from the group consisting of:

8. The method of claim 7 wherein said compound is

9. The method of claim 7 wherein said compound is

10. The method of claim 7 wherein said compound is

11. The method of claim 10 wherein said compound is

12. A method for delivering 2-amino-6-methyl-thiazine to mitochondria comprising contacting the mitochondria with a compound selected from the group consisting of:

13. The method of claim 12 wherein said compound is

14. The method of claim 13 wherein said compound is