Immunomodulatory properties of novel nucleotide oligomerization domain 2 (nod2) agonistic desmuramyldipeptides.
There is a pressing need for the development of novel adjuvants for human use. The minimal bioactive structure of bacterial peptidoglycan (PGN), muramyldipeptide (MDP), and its derivative murabutide (MB) have long been known for their adjuvant activities. For this reason, a series of novel desmuramyldipeptides have been designed and synthesized as part of our search for therapeutically useful MDP analogues. Since nucleotide oligomerization domain 2 (Nod2) is a putative receptor for MDP, we used engineered HEK293 cells overexpressing Nod2 to screen and validate our compounds for their Nod2-agonist activity. Their immunomodulatory properties were subsequently assessed in vitro by evaluating their effect on proinflammatory cytokine production of phorbol 12-myristate 13-acetate (PMA)/ionomycin-stimulated human peripheral blood mononuclear cells (PBMCs). Herein, we present novel desmuramyldipeptides, the most active of them possessing immunoenhancing properties as a result of their potent Nod2-agonistic effect.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. ziga.jakopin@ffa.uni-lj.si
Žiga
Ž
Jakopin
Martina
M
Gobec
Irena
I
Mlinarič-Raščan
Marija
M
Sollner Dolenc
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists*; D013997:Time Factors
D016207:Cytokines; D004151:Dipeptides; D007155:Immunologic Factors; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide