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 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.
1 . A composition for delivering cargo to a mitochondria comprising:
a. a membrane active peptidyl fragment having a high affinity with the mitochondria; and
b. cargo.
2 - 77 . (canceled)
78 . A compound having the structure:
in which R1 is a cargo, R2 and R3 are independently one of a tert-butyl oxycarbonyl (t-Boc) and a benzyloxycarbonyl (Cbz) group, and A is one of
where R4 is H, F or methyl.
79 . The compound of claim 78 having the structure:
80 . The compound of claim 78 having the structure:
81 . The compound of claim 78 having the structure:
82 . The compound of claim 78 in which R1 is a reactive oxygen species (ROS) scavenger.
83 . The compound of claim 82 in which the ROS scavenger comprises a nitroxide radical.
84 . The compound of claim 78 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).
85 . The compound of claim 78 , having the structure:
86 . The compound of claim 85 , having the structure:
87 . The compound of claim 85 having the structure:
88 . The compound of claim 85 having the structure:
89 . The compound of claim 85 in which R1 is a reactive oxygen species (ROS) scavenger.
90 . The compound of claim 89 in which the ROS scavenger comprises a nitroxide radical.
91 . The compound of claim 85 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).
92 . A method for delivering a cargo to mitochondria comprising contacting the mitochondria with a compound having the structure:
in which R1 is a cargo, R2 and R3 are independently one of a tert-butyl oxycarbonyl (t-Boc) and a benzyloxycarbonyl (Cbz) group, and A is one of
where R4 is H, F or methyl.
93 . The method of claim 92 , the compound having the structure:
94 . The method of claim 92 , the compound having the structure:
95 . The method of claim 92 , the compound having the structure:
96 . The method of claim 92 in which R1 is a reactive oxygen species (ROS) scavenger.
97 . The method of claim 96 in which the ROS scavenger comprises a nitroxide radical.
98 . The method of claim 92 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).
99 . The method of claim 92 , the compound having the structure:
100 . The method of claim 99 , the compound having the structure:
101 . The method of claim 99 , the compound having the structure:
102 . The method of claim 99 , the compound having the structure:
103 . The method of claim 99 in which R1 is a reactive oxygen species (ROS) scavenger.
104 . The method of claim 103 in which the ROS scavenger comprises a nitroxide radical.
105 . The method of claim 99 in which R1 is 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT).