title: Lipophilic Muramyl Dipeptide-Antigen Conjugates as Immunostimulating Agents.
abstract: Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment capable of triggering the innate immune system through interaction with the intracellular NOD2 receptor. To develop synthetic vaccine modalities composed of an antigenic entity (typically a small peptide) and a molecular adjuvant with well-defined activity, we previously assembled covalent MDP-antigen conjugates. Although these were found to be capable of stimulating the NOD2 receptor and were processed by dendritic cells (DCs) leading to effective antigen presentation, DC maturation--required for an apt immune response--could not be achieved with these conjugates. To improve the efficacy of these vaccine modalities, we equipped the MDP moiety with lipophilic tails, well-known modifications to enhance the immune-stimulatory activity of MDPs. Herein we report the design and synthesis of a lipophilic MDP-antigen conjugate and show that it is a promising vaccine modality capable of stimulating the NOD2 receptor, maturing DCs, and delivering antigen cargo into the MHC-I cross-presentation pathway.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands.
authors.forename: Marian M J H P
authors.initials: MM
authors.lastname: Willems
authors.affiliation: Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, the Netherlands.
authors.forename: Gijs G
authors.initials: GG
authors.lastname: Zom
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Meeuwenoord
authors.affiliation: Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, the Netherlands.
authors.forename: Selina
authors.initials: S
authors.lastname: Khan
authors.affiliation: Leiden University Medical Centre, Albinusdreef 2, 2300 RC, Leiden, the Netherlands.
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands.
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands. filippov@chem.leidenuniv.nl.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Filippov
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands. jcodee@chem.leidenuniv.nl.
authors.forename: Jeroen D C
authors.initials: JD
authors.lastname: Codée
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000737:chemistry* / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000941:Antigens / Q000737:chemistry* / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D057927:Hydrophobic and Hydrophilic Interactions; D018796:Immunoconjugates / Q000737:chemistry*; D015394:Molecular Structure; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D013329:Structure-Activity Relationship
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D018796:Immunoconjugates; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine
keywords: NOD2 receptor; conjugates; innate immunity; muramyl dipeptides; vaccines