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 bicyclic peptide of Formula II:
wherein
R 1 is a hydrophobic moiety;
R 2 is an aryl moiety;
R 3 is a neutral or hydrophilic moiety;
R 5 is an aryl moiety;
R 6 is a hydrophilic moiety;
R 7 is H, unsubstituted C1-2 alkyl, or C1-2 alkyl substituted with OH, SH, NH2, or CO2H;
R 8 is a hydrophilic moiety;
R 9 is CH2Imidazole, or C1-6 alkyl, benzyl, or phenyl substituted with one or more halo, OH, SH, CO2H, or NH2 groups;
R 11 is OH, NH2, R 12 , or NHR 12 , where R 12 is an amino acid residue, or substituted or unsubstituted, branched or straight chain C 1-20 alkyl, substituted or unsubstituted, branched or straight chain OC 1-20 alkyl, or a functionalized peptide side moiety of from 2 to 10 amino acid residues in length, any of which is optionally coupled to a detectable moiety or therapeutic moiety.
2. The bicyclic peptide of claim 1 , wherein R 1 is phenyl, benzyl, or substituted or unsubstituted, branched or straight chain C 1-20 alkyl.
3. The bicyclic peptide of claim 1 , wherein R 2 is unsubstituted phenyl or benzyl, or phenyl or benzyl substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
4. The bicyclic peptide of claim 1 , wherein R 2 is benzyl (CH 2 C 6 H 6 ), 4-hydroxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl, or 3,4-difluorobenzyl.
5. The bicyclic peptide of claim 1 , wherein R 3 is H, unsubstituted C 1-6 alkyl or C 1-6 alkyl substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
6. The bicyclic peptide of claim 1 , wherein R 3 is —CH 2 OH, —CHOHCH 3 , —CH 2 SH, —CH 2 CO 2 , —(CH 2 ) 2 CO 2 H, —(CH 2 ) 4 NH 2 , or —CH 2 CONH 2 .
7. The bicyclic peptide of claim 1 , wherein R 3 is —CH 3 or —CH 2 OH.
8. The bicyclic peptide of claim 1 , wherein R 3 is a peptide having from 2 to 8 natural and/or unnatural amino acid residues.
9. The bicyclic peptide of claim 1 , wherein R 3 is a tripeptide having natural or unnatural amino acid residues.
10. The bicyclic peptide of claim 1 , wherein R 5 is unsubstituted phenyl, benzyl, heteroaryl or CH 2 heteroaryl, or phenyl, benzyl, heteroaryl or —CH 2 heteroaryl substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
11. The bicyclic peptide of claim 1 , wherein R 6 is CH 2 Imidazole, or C 1-6 alkyl, benzyl, or phenyl substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
12. The bicyclic peptide of claim 1 , wherein R 8 is C 1-6 alkyl substituted with one or more halo, OH, SH, CO 2 H, or NH 2 groups.
13. The bicyclic peptide of claim 1 , wherein R 8 is —(CH 2 ) 4 NH 2 .
14. The bicyclic peptide of claim 1 , wherein R 9 is CH 2 Imidazole.
15. The bicyclic peptide of claim 1 , wherein R 11 is arginine, lysine, aspartic acid, phenylalanine, norleucine, or a peptide comprising arginine, lysine, aspartic acid, phenylalanine, or norleucine.
16. The bicyclic peptide of claim 1 wherein the compound has Formula II-A,
wherein
R 12 is H or is an amino acid residue, or substituted or unsubstituted, branched or straight chain C 1-20 alkyl, substituted or unsubstituted, branched or straight chain OC 1-20 alkyl, or a functionalized peptide side moiety of from 2 to 10 amino acid residues in length, wherein any of amino acid residue, or substituted or unsubstituted, branched or straight chain C 1-20 alkyl, substituted or unsubstituted, branched or straight chain OC 1-20 alkyl, or a functionalized peptide side moiety of from 2 to 10 amino acid residues in length is optionally coupled to a detectable moiety or therapeutic moiety.
17. The bicyclic peptide of claim 1 , wherein the peptide is chosen from C1-2 through C1-5, C1-12 through C1-21, C1-29 through C1-73, or from C1-74-1 through C1-74-6.
18. A method for treatment of an inflammatory disorder, the method comprising the step of administering a therapeutically effective amount of any of the compounds of claim 1 to a subject identified as having a need for treatment of the disorder.
19. A method for treatment of an autoimmune disorder, the method comprising the step of administering a therapeutically effective amount of any of the compounds of claim 1 to a subject identified as having a need for treatment of the disorder.
20. A method for treatment of a disorder of uncontrolled cellular proliferation, the method comprising the step of administering a therapeutically effective amount of any of the compounds of claim 1 to a subject identified as having a need for treatment of the disorder.