COMPOSITIONS AND METHODS FOR TREATING CONDITIONS ASSOCIATED WITH ALTERED TCA CYCLE METABOLISM
Compositions and methods for treating conditions associated with altered TCA cycle metabolism are provided.
1 - 95 . (canceled)
96 . A compound comprising:
one or more TCA cycle intermediates or prodrugs thereof; and
one or more non-naturally-occurring amino acids.
97 . The compound of claim 96 , wherein the one or more non-naturally-occurring amino acids comprise a non-naturally-occurring derivative of cysteine.
98 . The compound of claim 97 , wherein the one or more TCA cycle intermediates or prodrugs thereof comprise succinate.
99 . The compound of claim 98 , wherein the succinate is covalently linked via a terminal carbon of the succinate to the non-naturally-occurring derivative of cysteine.
100 . The compound of claim 98 , wherein the compound comprises two non-naturally occurring derivatives of cysteine that are the same or different, and wherein the succinate is covalently linked via a first terminal carbon of the succinate to a first of the two non-naturally-occurring derivatives of cysteine and is covalently linked via a second terminal carbon of the succinate to a second of the two non-naturally-occurring derivatives of cysteines
101 . The compound of claim 96 , wherein the compound further comprises a naturally-occurring amino acid.
102 . The compound of claim 101 , wherein the naturally-occurring amino acid is serine.
103 . The compound of claim 102 , wherein the non-naturally-occurring amino acid is a non-naturally-occurring derivative of cysteine.
104 . The compound of claim 103 , wherein the one or more TCA cycle intermediates or prodrugs thereof comprise succinate.
105 . The compound of claim 104 , wherein the succinate is covalently linked via a first terminal carbon of the succinate to the serine and is covalently linked via a second terminal carbon of the succinate to the non-naturally-occurring derivative of cysteine.
106 . A method of treating a condition associated with altered TCA cycle metabolism in a subject, the method comprising providing to a subject having a condition associated with altered TCA cycle metabolism a compound comprising:
one or more TCA cycle intermediates or prodrugs thereof; and
one or more non-naturally-occurring amino acids.
107 . The method of claim 106 , wherein the one or more non-naturally-occurring amino acids comprise a non-naturally-occurring derivative of cysteine.
108 . The method of claim 107 , wherein the one or more TCA cycle intermediates or prodrugs thereof comprise succinate.
109 . The method of claim 108 , wherein the succinate is covalently linked via a terminal carbon of the succinate to the non-naturally-occurring derivative of cysteine.
110 . The method of claim 108 , wherein the compound comprises two non-naturally occurring derivatives of cysteine that are the same or different, and wherein the succinate is covalently linked via a first terminal carbon of the succinate to a first of the two non-naturally-occurring derivatives of cysteine and is covalently linked via a second terminal carbon of the succinate to a second of the two non-naturally-occurring derivatives of cysteines
111 . The method of claim 106 , wherein the compound further comprises a naturally-occurring amino acid.
112 . The method of claim 111 , wherein the naturally-occurring amino acid is serine.
113 . The method of claim 112 , wherein the non-naturally-occurring amino acid is a non-naturally-occurring derivative of cysteine.
114 . The method of claim 113 , wherein the one or more TCA cycle intermediates or prodrugs thereof comprise succinate.
115 . The method of claim 114 , wherein the succinate is covalently linked via a first terminal carbon of the succinate to the serine and is covalently linked via a second terminal carbon of the succinate to the non-naturally-occurring derivative of cysteine.
116 . The method of claim 106 , wherein the condition associated with altered TCA cycle metabolism is selected from the group consisting of an inherited disorder, a neurodegenerative disorder, a cancer, an energetic disorder, refractory epilepsy, propionic acidemia (PA), methylmalonic acidemia (MMA), a long chain fatty acid oxidation disorder, succinyl CoA lyase deficiency, pyruvate carboxylase deficiency, mitochondrial respiratory chain deficiency, glutaric acidemia type 1 or type 2 a neurologic disease, disorder or condition, a pain or fatigue disease, muscular dystrophy, mitochondrial myopathy, mitochondrial encephalomyopathy lactic acidosis and stroke-like syndrome (MELAS), myoclonic epilepsy and ragged-red fibers (MERRF), a mitochondrial associated disease, and a disorder related to POLG mutation.