title: Single-step grafting of aminooxy-peptides to hyaluronan: a simple approach to multifunctional therapeutics for experimental autoimmune encephalomyelitis.
abstract: The immune response to antigens is directed in part by the presence or absence of costimulatory signals. The ability to coincidently present both antigen and, for example, a peptide that inhibits or activates the costimulatory pathway, would be a valuable tool for tolerization or immunization, respectively. A simple reaction scheme utilizing oxime chemistry was identified as a means to efficiently conjugate different peptide species to hyaluronan. Peptides synthesized with an aminooxy N-terminus reacted directly to hyaluronan under slightly acidic aqueous conditions without the need for a catalyst. The resulting oxime bond was found to rapidly hydrolyze at pH2 releasing peptide, but was stable at higher pH values (5.5 and 7). Two different peptide species, a multiple sclerosis antigen (PLP) and an ICAM-1 ligand (LABL) known to block immune cell stimulation, were functionalized with the aminooxy end group. These peptides showed similar reactivity to hyaluronan and were conjugated in an equimolar ratio. The resulting hyaluronan with grafted PLP and LABL significantly inhibited disease in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Aminooxy-peptides facilitate simple synthesis of multifunctional hyaluronan graft polymers, thus enabling novel approaches to antigen-specific immune modulation.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, 2030 Becker Dr, Lawrence, KS 66047, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Sestak
authors.forename: Meagan
authors.initials: M
authors.lastname: Mullins
authors.forename: Laura
authors.initials: L
authors.lastname: Northrup
authors.forename: Sharadvi
authors.initials: S
authors.lastname: Thati
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
authors.forename: Teruna J
authors.initials: TJ
authors.lastname: Siahaan
authors.forename: Cory
authors.initials: C
authors.lastname: Berkland
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006820:Hyaluronic Acid / Q000737:chemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000941:Antigens; D018991:Myelin Proteolipid Protein; D010455:Peptides; D018799:Intercellular Adhesion Molecule-1; D006820:Hyaluronic Acid
references.citation: ACS Chem Biol. 2007 Apr 24;2(4):252-62
references.pmid: 17432821
references.citation: Biomacromolecules. 2006 Jun;7(6):1781-9
references.pmid: 16768398
references.citation: Nature. 2001 Jun 28;411(6841):1058-64
references.pmid: 11429607
references.citation: Wound Repair Regen. 2010 May-Jun;18(3):302-10
references.pmid: 20412551
references.citation: Immunol Rev. 1990 Jun;115:243-50; discussion 251
references.pmid: 1697280
references.citation: Chem Biol Drug Des. 2010 Sep 1;76(3):234-44
references.pmid: 20572813
references.citation: J Pept Sci. 2000 Jun;6(6):290-9
references.pmid: 10912909
references.citation: Cancer Immunol Immunother. 1995 Sep;41(3):185-92
references.pmid: 7553688
references.citation: Peptides. 2001 Dec;22(12):1955-62
references.pmid: 11786177
references.citation: Chem Biol Drug Des. 2007 Sep;70(3):227-36
references.pmid: 17718717
references.citation: Eur J Immunol. 1995 Oct;25(10):2932-9
references.pmid: 7589094
references.citation: Tissue Eng Part A. 2011 Jul;17(13-14):1663-73
references.pmid: 19196133
references.citation: Nat Chem. 2009 Nov;1(8):611-22
references.pmid: 20161474
references.citation: Angew Chem Int Ed Engl. 2008;47(39):7523-6
references.pmid: 18712739
references.citation: Biomacromolecules. 2010 Sep 13;11(9):2247-54
references.pmid: 20704177
references.citation: Biomaterials. 2004 Aug;25(19):4797-804
references.pmid: 15120526
references.citation: Chem Commun (Camb). 2012 Apr 18;48(31):3781-3
references.pmid: 22430760
references.citation: Bioconjug Chem. 1999 Sep-Oct;10(5):755-63
references.pmid: 10502340
references.citation: J Biomed Mater Res. 1999 Nov;47(2):152-69
references.pmid: 10449626
references.citation: Pharmaceutics. 2012 May 23;4(2):276-95
references.pmid: 24300232
references.citation: Clin Cancer Res. 2000 May;6(5):1693-701
references.pmid: 10815887
references.citation: J Immunol. 1995 Dec 15;155(12):5608-16
references.pmid: 7499844
references.citation: J Immunol. 1989 Aug 15;143(4):1239-44
references.pmid: 2473123
references.citation: ACS Nano. 2011 Mar 22;5(3):1693-702
references.pmid: 21375342
references.citation: Pediatr Res. 1992 Oct;32(4):376-85
references.pmid: 1437386
references.citation: Biomacromolecules. 2008 Nov;9(11):2984-8
references.pmid: 18826275
references.citation: Cancer Res. 1994 Jan 1;54(1):197-203
references.pmid: 8261439
references.citation: J Immunol. 1985 Jul;135(1):423-7
references.pmid: 3889155
references.citation: Clin Immunol. 2008 Oct;129(1):69-79
references.pmid: 18676182
references.citation: Med Res Rev. 2012 Jul;32(4):727-64
references.pmid: 21433035
references.citation: Mol Immunol. 1996 Dec;33(17-18):1377-88
references.pmid: 9171897
references.citation: Bioconjug Chem. 2006 Sep-Oct;17(5):1360-3
references.pmid: 16984148
references.citation: J Control Release. 2007 Oct 8;122(3):279-86
references.pmid: 17599628
references.citation: Clin Cancer Res. 2004 Feb 1;10(3):916-23
references.pmid: 14871967
references.citation: Bioconjug Chem. 2012 Mar 21;23(3):574-85
references.pmid: 22372643
references.citation: Biopolymers. 2010;94(4):397-404
references.pmid: 20593471
references.citation: Chem Commun (Camb). 2008 Jun 21;(23):2591-611
references.pmid: 18535687
references.citation: J Control Release. 2011 Jun 10;152(2):232-40
references.pmid: 21315118
references.citation: Glycoconj J. 2007 Apr;24(2-3):157-65
references.pmid: 17268859
references.citation: Org Lett. 2006 Mar 2;8(5):827-9
references.pmid: 16494451
references.citation: J Control Release. 1999 May 1;59(1):77-86
references.pmid: 10210724
references.citation: J Biomed Mater Res A. 2012 Jan;100(1):84-93
references.pmid: 21972074
references.citation: Proc Natl Acad Sci U S A. 1976 Oct;73(10):3671-5
references.pmid: 62364
references.citation: Bioconjug Chem. 2008 Jan;19(1):145-52
references.pmid: 17997512
references.citation: Angew Chem Int Ed Engl. 2006 Apr 3;45(15):2348-68
references.pmid: 16557636
references.citation: J Exp Med. 1985 Aug 1;162(2):768-73
references.pmid: 2410534
references.citation: Eur J Pharm Sci. 2009 May 12;37(2):141-50
references.pmid: 19429421
references.citation: J Biol Chem. 2006 Nov 17;281(46):34936-41
references.pmid: 16959784
references.citation: Biomaterials. 2006 Sep;27(27):4698-705
references.pmid: 16750564
references.citation: Curr Org Chem. 2010 Jan;14(2):138-147
references.pmid: 20622973