Convergent Synthesis of Novel Muramyl Dipeptide Analogues: Inhibition of Porphyromonas gingivalis-Induced Pro-inflammatory Effects by High Doses of Muramyl Dipeptide

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 dec...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-07, Vol.59 (14), p.6878-6890
Main Authors: Cai, Bin, Panek, James S, Amar, Salomon
Format: Article
Language:English
Subjects:
Acetylmuramyl-Alanyl-Isoglutamine - administration & dosage
Acetylmuramyl-Alanyl-Isoglutamine - chemical synthesis
Acetylmuramyl-Alanyl-Isoglutamine - pharmacology
Animals
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Cell Line
Dose-Response Relationship, Drug
Inflammation - drug therapy
Inflammation - metabolism
Mice
Mice, Inbred C57BL
Molecular Structure
Porphyromonas gingivalis - drug effects
Porphyromonas gingivalis - metabolism
Shock, Septic - chemically induced
Shock, Septic - drug therapy
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00681