Cyclic peptides as protein targeting agents
Peptides having activity as protein binding agents are disclosed. The peptides have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R, R 1 , L 1 , L 2 , G, M, Y 1 Y 2 and SEQ are as defined herein. Methods associated with preparation and use of such peptides, as well as pharmaceutical compositions comprising such peptides, are also disclosed.
1. A cyclic peptide having the following structure (I):
or a salt, tautomer or stereoisomer thereof, wherein:
L 1 and L 2 are each individually optionally substituted linker moieties, each linker moiety optionally comprising a linkage to a solid support, a linkage to a reporter moiety, a linkage to a peptide ligand, a linkage to an azide or alkyne moiety or combinations thereof;
G is a triazole;
M is methionine;
R is H, -L 3 -A or C(═O)-L 3 -A, wherein L 3 is a linker moiety and A is an alkyne or an azide, or wherein L 3 is a linker moiety comprising triazole and A is a bond to a peptide ligand;
R 1 is H or C 1 -C 6 alkyl;
y 1 and y 2 are each individually 0 or 1; and
SEQ is an amino acid sequence comprising from 2 to 20 amino acids selected from the group consisting of: D-alanine, glycine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tryptophan, D-arginine, D-histidine, D-lysine, D-aspartate, D-glutamate, D-asparagine, D-glutamine, D-serine, D-threonine, D-tyrosine, D-proline, L-alanine, L-leucine, L-isoleucine, L-valine, L-phenylalanine, L-tryptophan, L-arginine, L-histidine, L-lysine, L-aspartate, L-glutamate, L-asparagine, L-glutamine, L-serine, L-threonine, L-tyrosine, L-proline, hydroxyproline, carboxyglutamate, O-phosphoserine, homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium.
2. The cyclic peptide of claim 1 , wherein L 1 , L 2 , or both, comprise one or more substituents selected from alkyl, alkyne, azide and aminocarbonyl.
3. The cyclic peptide of claim 1 , wherein L 1 , L 2 , or both, comprise a linkage selected from a linkage to a solid support, a linkage to a reporter moiety and a linkage to a peptide ligand.
4. The cyclic peptide of claim 1 , wherein L 1 and L 2 are alkylene.
5. The cyclic peptide of claim 1 , wherein the cyclic peptide has the following structure (Ia):
wherein:
R 3 is H, a linkage to a solid support, a linkage to a reporter moiety, a linkage to a peptide ligand, a linkage to an azide or alkyne moiety or combinations thereof; and
x and y are each independently an integer from 1 to 8.
6. The cyclic peptide of claim 1 , wherein SEQ comprises from 2 to 9 amino acids.
7. The cyclic peptide of claim 6 , wherein SEQ comprises from 5 to 7 amino acids.
8. The cyclic peptide of claim 1 , wherein the amino acids are selected from D and L stereoisomers of Ala, Gly, Leu, Ile, Val, Phe, Trp, Arg, His, Lys, Asp, Glu, Asn, Gln, Ser, Thr, Tyr and Pro.
9. The cyclic peptide of claim 1 , wherein R is H or —C(═O)-L 3 -A, where L 3 is a linker moiety and A is a bond to a peptide ligand or an alkyne.
10. The cyclic peptide of claim 9 , wherein A is an alkyne.
11. The cyclic peptide of claim 1 , wherein SEQ has 90% sequence identity to an amino acid sequence comprising any one of SEQ ID NOS: 1-33.
12. The cyclic peptide of claim 11 , wherein SEQ comprises any one of SEQ ID NOS: 1-14.
13. The cyclic peptide of claim 1 , wherein y 1 and y 2 are each 0.
14. A composition comprising the cyclic peptide of claim 1 and a pharmaceutically acceptable carrier.
15. The cyclic peptide of claim 1 , wherein the cyclic peptide comprises a linkage to a reporter moiety, the reporter moiety selected from polyethylene glycol (PEG), biotin, thiol and fluorophores.
16. The cyclic peptide of claim 15 , wherein the fluorophores are selected from carboxyfluorescein (FAM), fluorescein isothiocyanate (FITC), Cyanine-5 (Cy5), tetramethylrhodamine (TRITC) and Carboxytetramethylrhodamine (TAMRA).
17. The cyclic peptide of claim 7 , wherein the amino acids are selected from D and L stereoisomers of Ala, Gly, Leu, Ile, Val, Phe, Trp, Arg, His, Lys, Asp, Glu, Asn, Gln, Ser, Thr, Tyr and Pro.