Selective targeting agents for mitochondria
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.
1. A method for delivering a moiety to mitochondria of a patient comprising administering to a patient a mitochondria-targeting compound comprising a membrane-active fragment of gramicidin S or an E-alkene isostere thereof conjugated to a moiety, wherein the gramicidin S fragment or E-alkene isostere thereof has the sequence Leu- D Phe-Pro-Val-Orn, and wherein the moiety is a reactive-oxygen species (ROS) scavenger.
2. The method of claim 1 , in which the gramicidin S fragment or E-alkene isostere thereof comprises a β-turn.
3. The method of claim 1 , in which an amine of the gramicidin S fragment or E-alkene isostere thereof is acylated.
4. The method of claim 1 , in which an amine of the gramicidin S fragment or E-alkene isostere thereof is acylated with Boc and/or Cbz.
5. The method of claim 1 , in which the moiety is a nitroxide reactive-oxygen species (ROS) scavenger.
6. The method of claim 1 , in which the moiety is TEMPO or 4-amino TEMPO.
7. The method of claim 1 , in which the moiety is conjugated to the compound of formula A:
where R is H or methyl.
8. The method of claim 7 , in which the moiety is TEMPO or 4-amino TEMPO.
9. The method of claim 1 , in which the compound is administered to treat a patient for a condition associated or caused by reactive oxygen species (ROS).
10. The method of claim 9 , in which the condition is hemorrhagic shock.
11. The method of claim 1 , wherein the gramicidin S fragment or E-alkene isostere thereof has the sequence Leu-(E)- D Phe-Pro-Val-Orn.
12. A compound comprising a membrane-active fragment of gramicidin S or an E-alkene isostere thereof conjugated to a moiety, wherein the gramicidin S fragment or E-alkene isostere thereof has the sequence Leu- D Phe-Pro-Val-Orn, and wherein the moiety is a reactive-oxygen species (ROS) scavenger.
13. The compound of claim 12 , in which the gramicidin S fragment or E-alkene isostere thereof comprises a β-turn.
14. The compound of claim 12 , in which an amine of the gramicidin S fragment or E-alkene isostere thereof is acylated.
15. The compound of claim 12 , in which an amine of the gramicidin S fragment or E-alkene isostere thereof is acylated with Boc and/or Cbz.
16. The compound of claim 12 , in which the moiety is a nitroxide reactive-oxygen species (ROS) scavenger.
17. The compound of claim 16 , in which the in which the moiety is TEMPO or 4-amino TEMPO.
18. The compound of claim 12 , wherein the gramicidin S fragment or E-alkene isostere thereof has the sequence Leu-(E)- D Phe-Pro-Val-Orn.
19. A method for delivering a moiety to mitochondria of a patient comprising administering to a patient a mitochondria-targeting compound, represented by Formula B:
conjugated to a moiety, and wherein the moiety is a reactive-oxygen species (ROS) scavenger.
20. The method of claim 19 , in which the moiety is TEMPO or 4-amino TEMPO.
21. A compound comprising Formula B:
conjugated to a moiety, and wherein the moiety is a reactive-oxygen species (ROS) scavenger.