title: Convergent Synthesis of Novel Muramyl Dipeptide Analogues: Inhibition of Porphyromonas gingivalis-Induced Pro-inflammatory Effects by High Doses of Muramyl Dipeptide.
abstract: Porphyromonas gingivalis (P.g.)-induced TNF-α can be affected by muramyl dipeptide (MDP) in a biphasic concentration-dependent manner. We found that in P.g.-exposed macrophages, treatment with 10 μg/mL of MDP (MDP-low) up-regulated TNF-α by 29%, while 100 μg/mL or higher (MDP-high) significantly decreased it (16% to 38%). MDP-high was found to affect the ubiquitin-editing enzyme A20 and activator protein 1 (AP1). An AP1 binding site was found in the promoter region of A20. A20 promoter activity was up-regulated after transfection of AP1 cDNA in cells. Four analogues of MDP (3-6) were prepared through a convergent strategy involving the synthesis of two unique carbohydrate fragments, 7a and 7b, using the peptide coupling reagents, EDCI and HOAt. Analogue 4 improved MDP function and P.g.-induced activities. We propose a new signaling pathway for TNF-α induction activated after exposing macrophages to both P.g. and MDP-high or analogue 4.
authors.affiliation: Department of Chemistry, Boston University, Metcalf Center for Science and Engineering , 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Chemistry, Boston University, Metcalf Center for Science and Engineering , 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
authors.forename: James S
authors.initials: JS
authors.lastname: Panek
authors.affiliation: Center for Anti-Inflammatory Therapeutics, Department of Molecular & Cell Biology, Boston University Goldman School of Dental Medicine , 650 Albany Street, Suite 343, Boston, Massachusetts 02118, United States.
authors.forename: Salomon
authors.initials: S
authors.lastname: Amar
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000119:Acetylmuramyl-Alanyl-Isoglutamine