Bicyclic peptidyl inhibitor of tumor necrosis factor-alpha
Anticachexin C1 inhibits the TNFα-TNFα receptor interaction. In this work, analogs of anticachexin C1 are disclosed. The resulting bicyclic peptides inhibit TNFα TNFα-induced cell death, NF-κB activation, and c-Jun N-terminal kinase (JNK) signaling in cultured mammalian cells. Methods of using the bicyclic peptide anticachexin C1 analogs to treat cancer, inflammatory disorders and immune disorders are also described.
1. A compound comprising a bicyclic peptide of Formula 1:
wherein AA 1 -AA 3 and AA 5 -AA 10 are independently amino acid residues;
wherein R is null, carboxylic acid, amide, or C 1-20 keto, ester, an amino acid, or a functionalized peptide moiety of from 2 to 10 amino acid residues in length;
wherein n is an integer from 1 to 6;
wherein at least two of AA 1 , AA 2 , AA 3 , AA 5 , AA 7 , AA 8 , AA 9 , or AA 10 are independently amino acid residues with aryl or heteroaryl moieties; and
AA 6 is an amino acid with a hydrophilic moiety.
2. The compound of claim 1 , wherein AA 1 and AA 2 are independently amino acid residues comprising a hydrophobic moiety or an aryl moiety.
3. The compound of claim 2 , wherein the hydrophobic moiety is phenyl, unsubstituted C 1-20 alkyl, or C 1-20 alkyl independently substituted with one or more OH, SH, NH 2 or CO 2 H groups.
4. The compound of claim 2 , wherein the aryl moiety is unsubstituted phenyl or phenyl independently substituted with one or more halo, OH, SH, NH 2 or CO 2 H groups.
5. The compound of claim 2 , wherein AA 1 is a residue of phenylglycine or norleucine.
6. The compound of claim 2 , wherein AA 2 is a residue of tyrosine, 4-fluorophenylalanine, or phenylalanine.
7. The compound of claim 1 , wherein AA 3 comprises a neutral or hydrophilic moiety.
8. The compound of claim 7 , wherein the neutral or hydrophilic moiety is unsubstituted C 1-6 alkyl, or C 1-6 alkyl independently substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
9. The compound of claim 1 , wherein AA 3 is a residue of alanine, serine, threonine, or asparagine.
10. The compound of claim 1 , wherein n is 3.
11. The compound of claim 1 , wherein AA 5 is an amino acid residue comprising an aryl moiety.
12. The compound of claim 1 , wherein AA 5 is a residue of tyrosine, 4-fluorophenylalanine, or tryptophan.
13. The compound of claim 1 , wherein AA 6 is an amino acid residue comprising CH 2 Imidazole, C 1-6 alkyl, unsubstituted phenyl, or phenyl independently substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
14. The compound of claim 1 , wherein AA 7 is an amino acid residue comprising unsubstituted C 1-2 alkyl, or C 1-2 alkyl independently substituted with one or more OH, SH, NH 2 , or CO 2 H groups, or an amino acid residue wherein the side chain of the amino acid is H.
15. The compound of claim 1 , wherein AA 7 is a residue of glycine, sarcosine, alanine, or serine.
16. The compound of claim 1 , wherein AA 8 is an amino acid residue comprising a hydrophilic moiety.
17. The compound of claim 1 , wherein AA 8 is an amino acid residue comprising unsubstituted C 1-6 alkyl or C 1-6 alkyl independently substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
18. The compound of claim 1 , wherein AA 8 is a lysine residue.
19. The compound of claim 1 , wherein AA 9 is CH 2 Imidazole, or C 1-6 alkyl, phenyl substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
20. The compound of claim 1 , wherein AA 9 is a histidine residue.
21. The compound of claim 1 , wherein AA 3 comprises a side chain comprising a peptide of 2-8 amino acids in length.
22. The compound claim 21 , wherein the peptide of 2-8 amino acids in length comprises a structure of:
23. A method for treatment of an inflammatory disorder, the method comprising the step of administering a therapeutically effective amount of the compound of claim 1 to a subject identified as having a need for treatment of the disorder.
24. A method for treatment of an autoimmune disorder, the method comprising the step of administering a therapeutically effective amount of the compound of claim 1 to a subject identified as having a need for treatment of the disorder.
25. A method for treatment of a disorder of uncontrolled cellular proliferation, the method comprising the step of administering a therapeutically effective amount of the compound of claim 1 to a subject identified as having a need for treatment of the disorder.