Compositions and methods for treating mitochondrial neurogastrointestinal encephalopathy
Disclosed herein are compositions and methods of treating disclosure provides for compounds for use in treating Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE). In some embodiments, the compounds have cell penetrating activity and thymidine phosphorylase activity. In certain embodiments, the compounds disclosed herein comprise: a) at least one cell-penetrating peptide (CPP) moiety; and b) a thymidine phosphorylase, or an active fragment or analog thereof (TP), wherein the CPP is coupled, directly or indirectly, to TP.
1. A compound comprising
(a) thymidine phosphorylase, or an active fragment or analog thereof (TP), having an amino acid sequence that is at least 97% identical to any one of SEQ ID NOS: 1-13:
(b) at least one cyclic cell-penetrating peptide (CPP) having a structure of Formula III:
wherein:
each of AA 1 , AA 2 , AA 3 , AA 4 , AA u , and AA z is an amino acid;
m and n are independently selected from a number from 0 to 6; and
wherein the peptide of Formula III comprises at least two arginine and at least two hydrophobic amino acids; and
(c) at least one linker (L) that conjugates each CPP and the TP;
wherein each L is bound to the side chain of an amino acid on each CPP, and each of the L is also bound to the N-terminus of the TP or to the side chain of a lysine of the TP.
2. The compound of claim 1 , comprising a structure according to Formula V-A1, V-A2, or V-A3:
wherein q is an integer from 1 to 50.
3. The compound of claim 1 , comprising Formula V-B1 or V-B2:
4. The compound of claim 1 , comprising Formula V-B3 or V-B4:
5. The compound of claim 1 , further comprising at least one water-soluble polymer conjugated to the TP.
6. The compound of claim 5 , wherein the water-soluble polymer comprises a polyethylene glycol (PEG) residue.
7. The compound of claim 6 , wherein the PEG residue has a molecular weight ranging from about 1 kDa to about 20 kDa.
8. The compound of claim 1 , wherein the CPP has an amino acid sequence selected from any one of the amino acid sequence of SEQ ID NOS: 14-101, 108, 110, 124-127.
9. The compound of claim 1 , wherein the CPP comprises the amino acid sequence of SEQ ID NO: 27.
10. The compound of claim 1 , comprising Formula V-B3:
(V-B3), wherein the TP has the amino acid sequence of any one of SEQ ID NOS: 1-13.
11. The compound of claim 1 , Formula V-B4:
wherein the TP has the amino acid sequence of any one of SEQ ID NOS: 1-13.
12. The compound of claim 10 , wherein the TP has the amino acid sequence of SEQ ID NO: 3.
13. The compound of claim 11 , wherein the TP has the amino acid sequence of SEQ ID NO: 3.
14. The compound of claim 12 , further comprising at least one water-soluble polymer conjugated to the TP.
15. The compound of claim 14 , wherein the water-soluble polymer comprises a polyethylene glycol (PEG) residue with a molecular weight ranging from about 1 kDa to about 20 kDa.
16. The compound of claim 13 , further comprising at least one water-soluble polymer conjugated to the TP.
17. The compound of claim 16 , wherein the water-soluble polymer comprises a polyethylene glycol (PEG) residue with a molecular weight ranging from about 1 kDa to about 20 kDa.
18. The compound of claim 1 , comprising between 2 and 12 CPP.
19. The compound of claim 13 , comprising between 2 and 12 CPP.
20. The compound of claim 19 , comprising a polyethylene glycol (PEG) residue with a molecular weight ranging from about 1 kDa to about 20 kDa conjugated to the TP.
21. The compound of claim 20 , comprising 2 CPP.
22. The compound of claim 20 , comprising 3 CPP.
23. The compound of claim 20 , comprising 4 CPP.
24. The compound of claim 7 , wherein the PEG residue has a molecular weight of about 10 kDa.
25. The compound of claim 20 , wherein the PEG residue has a molecular weight of about 10 kDa.
26. A pharmaceutical composition comprising:
(a) a plurality of thymidine phosphorylases, or an active fragment or analog thereof (TP), each TP independently having an amino acid sequence that is at least 97% identical to any one of SEQ ID NOS: 1-13;
(b) at least one cyclic cell-penetrating peptide (CPP) comprising from 4 to 10 amino acids, wherein at least two amino acids are arginine and at least two amino acids are hydrophobic amino acids; and
(c) at least one linker (L) that conjugates each CPP and the TP;
wherein each L is bound to the side chain of an amino acid on each CPP, and each of the L is also bound to the N-terminus of the TP or to the side chain of a lysine in the TP.
27. The pharmaceutical composition of claim 26 , comprising between 2 and 12 CPP.
28. The pharmaceutical composition of claim 27 , comprising 2 CPP.
29. The pharmaceutical composition of claim 27 , comprising 3 CPP.
30. The pharmaceutical composition of claim 27 , comprising 4 CPP.
31. The pharmaceutical composition of claim 26 , wherein each TP independently further comprises at least one water-soluble polymer conjugated to the TP.
32. The pharmaceutical composition of claim 31 , wherein the water-soluble polymer comprises a polyethylene glycol (PEG) residue with a molecular weight ranging from about 1 kDa to about 20 kDa.
33. The pharmaceutical composition of claim 32 , wherein the PEG residue has a molecular weight of about 10 kDa.
34. The pharmaceutical composition of claim 33 , comprising a polyethylene glycol (PEG) residue with a molecular weight ranging from about 1 kDa to about 20 kDa conjugated to the TP.
35. The pharmaceutical composition of claim 34 , wherein the PEG residue has a molecular weight of about 10 kDa.