Glycosylated peptides with pseudoproline residues and having enhanced half-lives and ability to cross the blood brain barrier
Glycosylated peptides with glycosylation at or near the C-terminal domain of the peptide have an enhanced ability to cross the blood brain barrier (BBB) and/or enhanced half-lives. These glycosylated peptides may be used as drugs. For example, a PACAP peptide with a C-terminal glycosylation, e.g., in lieu of the terminal leucine, functions as a PAC 1 agonist with enhanced ability to cross the BBB and with enhanced half-life. The peptides can have a pseudoproline residue with glycosylation at or near the C-terminal domain.
1. A glycopeptide having at least one pseudoproline residue, wherein the glycopeptide is according to formula 1:
wherein A is an oxygen or a sulfur, R 1 is a first peptide chain, R 2 is a second peptide chain or —(C═O)NH 2 , R 3 is a hydrogen or methyl, and R 4 is a glycoside moiety,
wherein the first peptide chain or second peptide chain is an enkephalin, an endorphin, a dynorphin, a pituitary adenvlate cyclase-activatina nolvpentide (PACAP), an endogenous neuroDeDtide, a secretin family peptide, alamandine, or derivatives thereof,
wherein the pseudoproline residue is formed by hydrogen bonding of an amino functionality to the A being glycosidically bonded to the glycoside moiety,
wherein the glycopeptide has an increased ability to cross a blood brain barrier and an increased half life as compared to a version of the glycosylated peptide lacking a glycosylation.
2. The glycopeptide of claim 1 , wherein the glycoside moiety is a saccharide.
3. The glycopeptide of claim 2 , wherein the saccharide is a glucose, a maltose, a xylose, a lactose or a cellobiose.
4. The glycopeptide of claim 1 , wherein the glycopeptide is amphipathic.
5. The glycopeptide of claim 1 , wherein the glycoside moiety effectuates crossing of the glycopeptide by adsorption and desorption from a biological membrane.
6. The glycopeptide of claim 1 , wherein the glycopeptide is water-soluble.
7. The glycopeptide of claim 1 , wherein the glycopeptide is folded along the peptide side chain, wherein charged groups of the glycopeptide are disposed toward one end of the glycopeptide.
8. The glycopeptide of claim 1 , wherein the glycopeptide is helical.
9. A method for synthesizing a glycopeptide having at least one pseudoproline residue, wherein a conformation of the glycopeptide is according to formula 1:
wherein A is an oxygen or a sulfur, R 1 is a first peptide chain, R 2 is a second peptide chain or —(C═O)NH 2 , R 3 is a hydrogen or methyl, and R 4 is a glycoside moiety, said method comprising:
a. synthesizing a glycosidic bond between a saccharide and a reactive functional group of a carrier amino acid to form a glycosylated amino acid, wherein the carrier amino acid comprises A, R 2 , and R 3 , wherein the reactive functional group comprises A, and wherein the saccharide comprises R 4 ;
b. incorporating the glycosylated amino acid into an amino acid residue of R 1 ; and
c. effecting ring closure by spontaneously forming a hydrogen bond between a hydrogen atom of an amino group of the amino acid residue and the reactive functional group, A, to form a pseudoproline, thereby forming the properly oriented glycosylated peptide, wherein the first peptide chain or second peptide chain is an enkephalin, an endorphin, a dynorphin, a pituitary adenviate cyclase-activating polypeptide (PACAP), an endoaenous neuropeptide, a secretin family peptide, alamandine, or derivatives thereof.
10. The method of claim 9 , wherein the carrier amino acid is serine, threonine, cysteine, or extended alkyl derivatives thereof.
11. The method of claim 9 , wherein the reactive functional group is an —OH or —SH.
12. The method of claim 9 , wherein the saccharide is a glucose, a maltose, a lactose or a cellobiose.
13. The method of claim 9 , wherein the glycopeptide is amphipathic.
14. The method of claim 9 , wherein the saccharide effectuates crossing of the glycopeptide by adsorption and desorption from a biological membrane.
15. The method of claim 9 , wherein the glycopeptide is water-soluble.
16. The method of claim 9 , wherein the glycopeptide is folded along the side peptide chain such that charged groups of the glycopeptide are disposed on one end of the glycopeptide.
17. The method of claim 9 , wherein the glycopeptide is helical.
18. A composition of a glycopeptide having at least one pseudoproline residue, said composition of the glycopeptide comprising one of the following:
wherein HSDGIFTDSY 10 SRYRKQMAVK 20 KYLAAV=pituitary adenylate cyclase-activating peptide (PACAP 1.26 ) (SEQ ID NO: 10);
wherein FTDSY 10 SRYRKQMAVK 20 KYLAAV=pituitary adenylate cyclase-activating peptide (PACAP 6-26 )(SEQ ID NO: 11);
wherein FTDSY 10 SRYRKQMAVK 20 KYLAAV=pituitary adenylate cyclase-activating peptide (PACAP 6-26 ) (SEQ ID NO: 11), and lactose=(-β-D-Glc-β-D-Gal).