Compositions and methods for treating mitochondrial neurogastrointestinal encephalopathy
AssigneeEntrada Therapeutics, Inc.
InventorsNatarajan Sethuraman, Jason Ruth, Lou A. Tartaglia, Dehua Pei, Ziqing Qian
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Abstract
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.
Claims35
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 AA1, AA2, AA3, AA4, AAu, and AAz 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.
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.
Dependencies are inferred from the claim text.