Glycosylated peptides with pseudoproline residues and having enhanced half-lives and ability to cross the blood brain barrier
AssigneeArizona Board of Regents on Behalf of the University of Arizona
InventorsRobin Polt, Evan M. Jones, Bobbi Anglin, Michael L. Heien, John M. Streicher
Life of this patent
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Abstract
Glycosylated peptides with glycosyiatiou 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 PAC1 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.
Claims26
A glycopeptide having at least one pseudoproline residue, wherein the glycopeptide is according to formula 1:
- wherein A is an oxygen or a sulfur, R1 is a first peptide chain, R2 is a second peptide chain or —(C═O)NH2, R3 is a hydrogen or methyl, and R4 is a glycoside moiety,
- 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.
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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, R1 is a first peptide chain, R2 is a second peptide chain or —(C═O)NH2, R3 is a hydrogen or methyl, and R4 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, R2, and R3, wherein the reactive functional group comprises A, and wherein the saccharide comprises R4;
- b.incorporating the glycosylated amino acid into an amino acid residue of R1;
- 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.
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24-84. (canceled)
A composition of a glycopeptide having at least one pseudoproline residue, said composition of the glycopeptide comprising one of the following:
- wherein HSDGIFTDSY10SRYRKQMAVK20KYLAAV=pituitary adenylate cyclase-activating peptide (PACAP1-26) (SEQ ID NO:
- 10);
- wherein FTDSY10SRYRKQMAVK20KYLAAV=pituitary adenylate cyclase-activating peptide (PACAP6-26) (SEQ ID NO:
- 11);
- wherein FTDSY10SRYRKQMAVK20KYLAAV=pituitary adenylate cyclase-activating peptide (PACAP6-26) (SEQ ID NO:
- 11), and lactose=(-β-D-Glc-β-D-Gal);
- wherein DRVYIH=angiotensin peptide (Ang-(1-6)) (SEQ ID NO:
- 12);
- wherein DRVYIH=angiotensin peptide (Ang-(1-6)) (SEQ ID NO:
- 12), and lactose=(-β-D-Glc-β-D-Gal);
- wherein ARVYIH=angiotensin peptide (Ang-(1-6)) (SEQ ID NO:
- 21);
- or
- wherein ARVYIH=angiotensin peptide (Ang-(1-6)) (SEQ ID NO:
- 21), and lactose=(-β-D-Glc-β-D-Gal).
86-90. (canceled)
Dependencies are inferred from the claim text.