title: Structural requirements of acylated Gly-l-Ala-d-Glu analogs for activation of the innate immune receptor NOD2.
abstract: The fragment of bacterial peptidoglycan muramyl dipeptide (MDP) has long been known for its adjuvant activity, however the underlying mechanism of this action has only recently been elucidated. It is ascribed to its agonist action on the nucleotide-binding oligomerization domain-containing protein 2 (NOD2). In spite of the pressing need for novel adjuvants for human use, this discovery is hampered, by not knowing the structural requirements underlying the immunostimulatory activity. We have investigated how minor modifications of hit compound acyl Gly-L-Ala-D-Glu derivative I modulate the molecular recognition by NOD2. A series of novel desmuramyldipeptides has been designed and synthesized leading to the identification of compound 16, in which the sugar moiety is replaced by a 6-phenylindole moiety, that exhibits the strongest NOD2 activation to date sans the carbohydrate moiety. The results have enabled a deeper understanding of the structural requirements of desmuramylpeptides for NOD2 activation.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI - 1000, Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI - 1000, Ljubljana, Slovenia.
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič-Raščan
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI - 1000, Ljubljana, Slovenia.
authors.forename: Marija Sollner
authors.initials: MS
authors.lastname: Dolenc
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI - 1000, Ljubljana, Slovenia. Electronic address: ziga.jakopin@ffa.uni-lj.si.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Jakopin
mesh_terms: D002460:Cell Line; D015195:Drug Design; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D007211:Indoles; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D009842:Oligopeptides; C000614245:diethyl (6-phenyl-1H-indole-2-carbonyl)glycyl-alanyl-glutamate
keywords: Desmuramylpeptide; Immunoadjuvant; Immunomodulator; Immunostimulant; Muramyl dipeptide; NOD2 agonist