Compositions and methods for treating mitochondrial neurogastrointestinal encephalopathy

1. A compound having a stricture according to Formula I-A:

CPP-L-TP   (I-A),

wherein:

CPP is a cyclic cell-penetrating peptide (cCPP);

TP is thymidine phosphorylase, or an active fragment or analog thereof; and has an amino acid sequence that is at least 95% identical to SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;

L is a linker; and

wherein L is a covalently bound to the side chain of an amino acid on the CPP and to the N-terminus of the TP;

the cCPP has a sequence comprising any of Formula IV-A-D:

wherein:

each of AA H1 and AA H2 are independently a D or L hydrophobic aromatic amino acid;

at each instance and when present, each of AA U and AA Z are independently a D or L amino acid;

m and n are independently selected from a number from 0 to 6; and

wherein Formula IV-A-D comprise at least three consecutive arginine, and at least three-consecutive hydrophobic aromatic amino acids.

2. The compound of claim 1 , wherein L is: (a) one or more D or L amino acids, each of which is optionally substituted; (b) alkylene, alkenylene, alkynylene, carbocyclyl, or heterocyclyl, each of which is optionally substituted; or (c) —(R 1 —X—R 2 )z-, wherein each of R 1 and R 2 , at each instance, are independently selected from alkylene, alkenylene, alkynylene, carbocyclyl, and heterocyclyl, each X is independently NR 3 , —NR 3 C(O)—, S, and O, wherein R 3 is independently selected from H, alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl, wherein each alkylene, alkenylene, alkynylene, carbocyclyl, and heterocyclyl is optionally substituted, and wherein z is an integer from 1 to 20; or combinations thereof.

3. The compound of claim 1 , wherein L has a structure according to Formula II-A′ or II-B′:

and wherein

M is absent or a group bound to TP;

AA s is a side chain or terminus of an amino acid on the CPP;

o is an integer from 0 to 10;

p is an integer from 0 to 10;

q is an integer from 1 to 50; and

r is 0 or 1.

4. The compound of claim 3 , wherein M is present and comprises an alkylene, alkenylene, alkynylene, carbocyclyl, or heterocyclyl, each of which is optionally substituted.

5. The compound of claim 4 , wherein M is present and selected from the group consisting of:

wherein each R is independently an alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl.

6. The compound of claim 3 , wherein M is

7. The compound of claim 4 , wherein M is present and is covalently bound to the N-terminus TP.

8. The compound of claim 1 , wherein the compound has a structure according to Formula V-A1, V-A2, or V-A3:

wherein q is an integer from 10-15.

9. The compound of claim 1 , wherein the TP has the amino acid sequence of SEQ ID NO. 1.

10. The compound of claim 1 , wherein the TP has the amino acid sequence of SEQ ID NO. 2.

11. The compound of claim 1 , wherein the TP has the amino acid sequence of SEQ ID NO. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

12. The compound of claim 1 , wherein the TP has the amino acid sequence of SEQ ID NO, 3.

13. The compound of claim 1 , further comprising a water-soluble polymer conjugated to the TP.

14. The compound of claim 13 , wherein the water-soluble polymer comprises a polyethylene glycol (PEG) residue.

15. The compound of claim 14 , wherein the PEG residue has a molecular weight ranging from about 1 kDa to about 20 kDa.

16. The compound of claim 1 , wherein the hydrophobic aromatic amino acid are independently, selected from piperidine-2-carboxylic acid, naphthylalanine, tryptophan, and phenylalanine, each of which is optionally substituted with one or more substituents.

17. The compound of claim 1 , wherein the sum of m and n is from 2 to 6; and Formula IV-A-D comprise at least four consecutive arginine, at least three consecutive hydrophobic aromatic amino acids and at least three adjacent amino acids having alternating chirality.

18. The compound of claim 1 , wherein the cCPP has the amino acid sequence selected from SEQ ID NO. 21, 27 or 124.