VE-CADHERIN BINDING BIOCONJUGATE
This disclosure provides bioconjugate comprising a glycan and at least one peptide comprising a VE-Cadherin binding unit conjugated thereto, compositions comprising the same, and methods of use thereof.
1 . A bioconjugate comprising a glycan and at least one peptide comprising a VE-Cadherin binding unit conjugated thereto.
2 . The bioconjugate of claim 1 , wherein the peptide comprises an amino acid sequence GHRPLDKKREEAPSLRPA (SEQ ID NO:2), or an amino acid sequence having one, two, or three amino acid addition, deletion and/or substitution(s) therefrom.
3 . The bioconjugate of claim 1 , wherein the peptide comprises up to about 50, or about 40, or about 30, or about 20 amino acids.
4 . The bioconjugate of claim 1 , wherein the peptide comprises an amino acid sequence GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID NO:3), or an amino acid sequence having one, two, or three amino acid addition, deletion and/or substitution therefrom.
5 . The bioconjugate of claim 1 , further comprising at least one selectin-binding unit, ICAM-binding unit, VCAM-binding unit, and/or collagen-binding unit.
6 . The bioconjugate of claim 1 , wherein the glycan is selected from the group consisting of alginate, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparan, heparan sulfate, heparin, dextran, dextran sulfate, and hyaluronan, or a derivative thereof.
7 . The bioconjugate of claim 1 , wherein the glycan is heparin.
8 . The bioconjugate of claim 1 , wherein the glycan is dermatan sulfate.
9 . The bioconjugate of claim 1 , wherein the glycan is hyaluronan.
10 . The bioconjugate of claim 1 , comprising from 1 to about 25 peptides, or from about 5 to about 25 peptides, or from about 1 to about 15 peptides, or about 2 peptides, or about 5 peptides, or about 10 peptides, or about 15 peptides.
11 . The bioconjugate of claim 1 , comprising from 50 to about 80 peptides, or from about 60 to about 70 peptides.
12 . The bioconjugate of claim 1 , wherein the glycan comprises:
a) from about 1 to about 75 percent (%) functionalization,
b) from about 5 to about 30 percent (%) functionalization,
c) from about 10 to about 40 percent (%) functionalization,
d) about 25 percent (%) functionalization, or
e) about 30 percent (%) functionalization,
wherein the percent (%) functionalization is determined by a percent of disaccharide units on the glycan which are functionalized with peptide.
13 . The bioconjugate of claim 1 , wherein the peptide is bound to the glycan via a spacer.
14 . The bioconjugate of claim 13 , wherein peptide is bound to the glycan via a spacer at the peptide N-terminus.
15 . The bioconjugate of claim 13 , wherein peptide is bound to the glycan via a spacer at the peptide C-terminus.
16 . The bioconjugate of claim 1 , wherein the peptide is bound to the glycan via a spacer and the spacer comprises between about 5 to about 50 carbon atoms.
17 . The bioconjugate of claim 1 , wherein the spacer comprises one or more amino acids selected from the group consisting of glycine, alanine, arginine, lysine and serine.
18 . The bioconjugate of claim 17 , wherein the spacer is selected from the group consisting of glycine, glycine-glycine, serine-glycine, lysine-arginine, arginine-arginine, and glycine-serine-glycine.
19 . The bioconjugate of claim 1 , wherein the peptide is bound to the glycan via a spacer and the spacer is branched.
20 . A composition comprising the bioconjugate of claim 1 and one or more bioconjugates selected from the group consisting of:
a) a bioconjugate comprising a glycan and at least one peptide comprising a selectin-binding unit;
b) a bioconjugate comprising a glycan and at least one peptide comprising a ICAM-binding unit;
c) a bioconjugate comprising a glycan and at least one peptide comprising a VCAM-binding unit; and
d) a bioconjugate comprising a glycan and at least one peptide comprising a collagen-binding unit.
21 . A composition comprising the bioconjugate of claim 1 and a bioconjugate comprising a glycan and at least one peptide comprising a collagen-binding unit.
22 . A composition comprising the bioconjugate of claim 1 , wherein the average number of peptide(s) per glycan is less than about 30.
23 . A composition comprising the bioconjugate of claim 1 , wherein the average percent functionalization of glycan with peptide(s) per about 30%.
24 . A composition comprising the bioconjugate of claim 1 , wherein the average number of peptide(s) per glycan is from about 5 to about 25.
25 . A composition comprising the bioconjugate of claim 1 , wherein the average number of peptide(s) per glycan is about 7.
26 . A pharmaceutical composition comprising the bioconjugate of claim 1 .
27 . A method for maintaining endothelial integrity in a patient in need thereof, comprising administering to the patient an effective amount of the bioconjugate of claim 1 .
28 . A method for treating a patient suffering from a disease associated with endothelial dysfunction comprising administering to the patient an effective amount of the bioconjugate of claim 1 .
29 - 40 . (canceled)
41 . A method for preventing or reducing inflammation at a vascular site in a patient, wherein the site (a) comprises permeated endothelial lining or damaged endothelial cells, and (b) is not undergoing or recovering from a vascular intervention procedure, the method comprising administering to the patient an effective amount of the bioconjugate of claim 1 .
42 . (canceled)
43 . A method for treating or preventing ischemic reperfusion injury in a patient in need thereof, comprising administering to the patient an effective amount of the bioconjugate of claim 1 .
44 - 46 . (canceled)
47 . A method of treating a fibrotic disease in a patient in need thereof, comprising administering to the patient an effective amount of the bioconjugate of claim 1 .
48 - 51 . (canceled)
52 . A method for treating a disease or disorder selected from the group consisting of osteoarthritis, cancer, neointimal hyperplasia (peripheral & coronary), an ophthalmologic disease or disorder, tissue scarring, acute systemic disorders, chronic wounds, ischemia/reperfusion injury, central nervous system (CNS) diseases, fibrotic conditions, and vasculitis, the method comprising administering to the patient an effective amount of the bioconjugate of claim 1 .