FAS peptide mimetics and uses thereof
View Patent ↗Exocyclic peptide mimetics that disable Fas were developed. A three dimensional model of the Fas receptor-ligand complex was constructed and structurally predicted regions of the receptor that were relevant to binding ligand were used to create constrained peptide mimetics. Exocyclic anti-Fas peptide mimetics were identified that block Fas receptor-ligand interactions, and modulate Fas biological activity both in vitro and in vivo. The mimetics are useful, e.g., for treating Fas-related pathologies.
1. A Fas mimetic represented by the formula (I)
wherein B 1 and B 9 are independently a peptide of 1-6 genetically encoded amino acids, at least one of which is a genetically encoded hydrophobic amino acid, or a genetically encoded aromatic amino acid,
Z 2 is cysteine, that forms a covalent linkage with B 1 , X 3 or X 4 and Z 8 ,
Z 8 is cysteine, that forms a covalent linkage with B 9 , X 7 and Z 2 ,
X 3 is a genetically encoded hydrophilic amino acid or null,
X 4 is aspartic acid or glutamic acid,
X 5 is aspartic acid or glutamic acid,
X 6 is selected from the group consisting of histidine, lysine, arginine, asparagine or glutamine,
X 7 is a genetically encoded aromatic amino acid
“ ” is a covalent linkage comprising an amide or a substituted amide thereof, and
“ ” is a covalent linkage,
or a pharmaceutically acceptable salt.
2. The mimetic of claim 1 wherein X 3 is null.
3. The mimetic of claim 2 wherein X 4 is aspartic acid and X 5 is glutamic acid.
4. The mimetic of claim 3 wherein X 7 is phenylalanine.
5. The mimetic of claim 4 wherein B 1 or B 9 is a genetically encoded aromatic amino acid.
6. The mimetic of claim 5 wherein each of B 1 and B 9 is a genetically encoded aromatic amino acid.
7. The mimetic of claim 5 wherein B 1 or B 9 is tyrosine.
8. The mimetic of claim 7 wherein each of B 1 and B 9 is tyrosine.
9. The mimetic of claim 1 wherein said mimetic has a K D for FasL of 10 −4 M or less.
10. The mimetic of claim 9 wherein said mimetic has a K D for FasL of 10 −5 M or less.
11. The mimetic of claim 1 wherein said mimetic has a k off for FasL of 10 −3 s −1 or less.
12. The mimetic of claim 1 wherein said mimetic has a k off for FasL of 10 −4 s −1 or less.
13. A pharmaceutical composition comprising a mimetic of claim 1 and a pharmaceutically acceptable excipient.
14. The pharmaceutical composition of claim 13 wherein said excipient is a member selected from the group consisting of a diluent, buffer, carrier, stabilizer and preservative.