FGF growth factor analogs
View Patent ↗The present invention provides a fibroblast growth factor heparin-binding analog of the formula: where R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.
1. A fibroblast growth factor heparin-binding analog of formula I:
wherein:
X comprises a sequence selected from SEQ ID NO 7, SEQ ID NO 25 or SEQ ID NO 26;
R 1 is either a single trifunctional amino acid residue covalently bonded to each X or is a dipeptide of the formula AA 1 -AA 2 wherein AA 1 -AA 2 are each a trifunctional amino acid;
R 2 is 0;
Each R 3 is hydrogen (H) such that the terminal group is NH 2 , or is an acyl group with a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain including an N-terminus NH 2 , NH 3 + , or NH group or a corresponding acylated derivative;
R 4 is present as NH 2 or H;
R 5 is OH, NH 2 , or an acyl group with a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain;
Y is a linker comprising Ahx-Ahx-Ahx; and
Z is selected from SEQ ID NO 2 or SEQ ID NO 5.
2. The compound of claim 1 wherein X and Z are synthetic peptide chains.
3. The compound of claim 1 wherein the compound of claim 1 has an avidity for heparin such that the compound of formula I binds heparin in 0.15 M NaCl, but is eluted by 1 M NaCl.
4. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
5. A medical device comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
6. The analog of claim 1 wherein the structure is: H-K(H-YRSRKYSSWYVALKR)-K(H-YRSRKYSSWYVALKR)-Ahx-Ahx-Ahx-RKRKLERIAR-NH 2
wherein YRSRKYSSWYVALKR (SEQ ID NO: 7) is X and RKRKLERIAR (SEQ ID NO: 2) is Z.
7. The analog of claim 1 wherein the structure is: H-K(H-RKLAVYWSSYKRSRY)-K(H-RKLAVYWSSYKRSRY)-Ahx-Ahx-Ahx-RKRKLERIAR-NH 2
wherein RKLAVYWSSYKRSRY (SEQ ID NO: 26) is X and RKRKLERIAR (SEQ ID NO: 2) is Z.
8. The analog of claim 1 wherein the structure is: H-K(H-AESGDDYCVLVFTDSAWTKICDWSHFRN)-K(H-AESGDDYCVLVFTDSAWTKICDWSHFRN)-Ahx-Ahx-Ahx-RKRKLERIAR-NH 2
wherein AESGDDYCVLVFTDSAWTKICDWSHFRN (SEQ ID NO: 25) is X and RKRKLERIAR (SEQ ID NO: 2) is Z.
9. A fibroblast growth factor heparin-binding analog of formula I:
wherein:
X is SEQ ID NO 7;
R 1 is a single trifunctional amino acid residue covalently bonded to each X when R 2 is 0;
R 2 is 0 peptide bonds;
Each R 3 is hydrogen (H) such that the terminal group is NH 2 , or is an acyl group with a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain including an N-terminus NH 2 , NH 3 + , or NH group or a corresponding acylated derivative;
R 4 is not present if R 1 is a single trifunctional amino acid residue;
R 5 is OH, NH 2 , or a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain;
Y is a linker Ahx-Ahx-Ahx; and
Z is SEQ ID NO 5.
10. The analog of claim 9 wherein the structure is: H-YRSRKYSSWYVALKRK(H-YRSRKYSSWYVALKR)-Ahx-Ahx-Ahx-RKRLDRIAR-NH 2
wherein YRSRKYSSWYVALKRK (SEQ ID NO: 7) is X and RKRLDRIAR (SEQ ID NO: 5) is Z.