Protein conjugates and methods for their preparation
Reductive amination of peptide-derived aldehydes with anilines or heteroarylamines containing a property-modifying group provides new, hydrolytically stable protein conjugates, suitable for therapy.
1. A conjugated peptide according to formula (I)
wherein
Prot is a peptide-derived radical, wherein said peptide-derived radical formed by the formal removal of a hydrogen atom from an amino group (—NH 2 ) of said peptide,
R 1 is arylene or a heteroarylene, optionally substituted with a C 1-6 -alkyl, halogen, cyano, nitro, hydroxyl, carboxyl, or aryl group;
R 2 is a linker comprising the diradical C(═O)—NH—, and
R 3 is a property-modifying group;
R 4 is hydrogen or C 1-6 -alkyl;
R 5 is —CH 2 — or —C(═O)—,
or pharmaceutically acceptable salts, thereof.
2. A compound according to claim 1 , wherein R 1 is a C 6-8 -arylene, a C 12-18 -arylene or a C 5-18 -heteroarylene, optionally substituted with a C 1-6 alkyl, halogen, cyano, nitro, hydroxyl. carboxyl, or aryl group.
3. A compound according to claim 1 , wherein R 2 is —C(═O)—NH—.
4. A compound according to claim 1 , wherein R 3 is a linear or branched polyethylene glycol (PEG), poloxamer, poly(lactic acid), poly(lactide)-glycolide copolymer, oligosaccharide, peptides, proteins, or combinations thereof, optionally substituted with acidic or negatively charged functional groups, with basic or cationic functional groups, or with combinations thereof.
5. A compound according to claim 4 , wherein R 3 is a linear or branched polyethylene glycol of a molecular weight of 5-60 kDa.
6. The peptide radical of R 5 -Prot in the conjugated peptide according to claim 1 , derived from a peptide-derived aldeyde or ketone of formula (A):
R 6 —C(═O)—R 5 -Prot, (A)
wherein,
R 5 is —CH 2 — or C(═O)—, and
R 6 is hydrogen or an optionally substituted α-carbon atom.
7. A compound according to claim 6 , wherein R 6 is hydrogen, C 1-6 -alkyl or C 1-6 -cycloalkyl.
8. A compound according to claim 1 , wherein Prot is a peptide-derived radical generated by the formal removal of a hydrogen atom from an amino group (—NH 2 ) of a peptide or protein, and wherein said amino group is the N-terminal amino group of the peptide, a side-chain amino group of lysine residue in the peptide, or a side-chain amino group of glutamine or asparagine (CONH2) residue in the peptide.
9. A compound according to claim 1 , wherein Prot is a growth hormone-derived radical.
10. A pharmaceutical preparation comprising a compound according to claim 9 .
11. A method of treating diseases benefiting from an increase in the level of circulating growth hormone, the method comprising the administration of a therapeutically effective amount of a compound according to claim 9 to a subject in need thereof, wherein said disease is growth hormone deficiency.