title: Activity of the HMGB1-derived immunostimulatory peptide Hp91 resides in the helical C-terminal portion and is enhanced by dimerization.
abstract: We have previously shown that an 18 amino acid long peptide, named Hp91, whose sequence corresponds to a region within the endogenous protein HMGB1, activates dendritic cells (DCs) and acts as adjuvant in vivo by potentiating Th1-type antigen-specific immune responses. We analyzed the structure-function relationship of the Hp91 peptide to investigate the amino acids and structure responsible for immune responses. We found that the cysteine at position 16 of Hp91 enabled formation of reversible peptide dimmers, monomer and dimmer were compared for DC binding and activation. Stable monomers and dimers were generated using a maleimide conjugation reaction. The dimer showed enhanced ability to bind to and activate DCs. Furthermore, the C-terminal 9 amino acids of Hp91, named UC1018 were sufficient for DC binding and Circular dichroism showed that UC1018 assumes an alpha-helical structure. The ninemer peptide UC1018 induced more potent antigen-specific CTL responses in vivo as compared to Hp91 and it protected mice from tumor development when used in a prophylactic vaccine setting. We have identified a short alpha helical peptide that acts as potent adjuvant inducing protective immune responses in vivo.
authors.affiliation: Rebecca and John Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: R
authors.initials: R
authors.lastname: Saenz
authors.forename: B
authors.initials: B
authors.lastname: Messmer
authors.forename: D
authors.initials: D
authors.lastname: Futalan
authors.forename: Y
authors.initials: Y
authors.lastname: Tor
authors.forename: M
authors.initials: M
authors.lastname: Larsson
authors.forename: G
authors.initials: G
authors.lastname: Daniels
authors.forename: S
authors.initials: S
authors.lastname: Esener
authors.forename: D
authors.initials: D
authors.lastname: Messmer
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008301:Maleimides; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008301:Maleimides; D010446:Peptide Fragments; C043592:maleimide
keywords: Adjuvant; Dendritic cells; Immune response; Peptide