A Novel Immunostimulator,N²-[α-O-Benzyl-N-(acetylmuramyl)-l-alanyl-d- isoglutaminyl]-N⁶-trans-(m-nitrocinnamoyl)-l-lysine, and Its Adjuvancy on the Hepatitis B Surface Antigen

Abstract

N(2)-[alpha-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N(6)-trans-(m-nitrocinnamoyl)-L-lysine (muramyl dipeptide C, or MDP-C) has been synthesized as a novel, nonspecific immunomodulator. The present study shows that MDP-C induces strong cytolytic activity by macrophages on P388 leukemia cells and cytotoxic activity by cytotoxic T lymphocytes (CTLs) on P815 mastocytoma cells. Our results also indicate that MDP-C is an effective stimulator for production of interleukin-2 and interleukin-12 by murine bone marrow derived dendritic cells (BMDCs) and production of interferon-gamma by CTLs. Additionally, MDP-C increases the expression levels of several surface molecules, including CD11c, MHC class I, and intercellular adhesion molecule-1 in BMDCs. Moreover, MDP-C remarkably enhances the immune system's responsiveness to hepatitis B surface antigen (HBsAg) in hepatitis B virus transgenic mice for both antibody production and specific HBsAg T-cell responses ex vivo. Our results indicate that MDP-C is an apyrogenic, nonallergenic, and low-toxicity immunostimulator with great potential for diagnostic, immunotherapeutic, and prophylactic applications in diseases such as hepatitis B and cancers.

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

“…When NOD agonists act as immunotherapeutics, they activate the cytotoxic potential of immune cells residing in the TME and, consequently, facilitate their engagement with cancer cells. Such enhancement of anticancer immunity has been investigated in the context of NOD2 agonists which, mainly, activate monocytes and macrophages although stimulation of NK cells and DCs has also been reported. In general, two possible mechanisms on how NOD agonists activate the antitumor activity of macrophages have been suggested.…”

“…Recently, MDP-C (22) was identified as a new MDP analog that mediated its immunostimulating effect through macrophages and DCs. 90 In a cell-based assay, 22 stimulated the cytotoxic activity of murine macrophages against P388 leukemia cells resulting in an inhibitory rate of 71%. In comparison, romurtide (11) used as a positive control demonstrated a much lower inhibitory rate of 45%.…”

Muramyl Dipeptide and its Derivatives: Peptide Adjuvant in Immunological Disorders and Cancer Therapy

“…N 2 -[α- O -benzyl- N -(acetylmuramyl)-L-alanyl-D-isoglutamyl]- N 6 - trans -( m -nitrocynnamoyl)-L-lysine; MDP-C could be synthesized in a similar way on an MBHA amide resin, and it induced strong cytolytic activity by macrophages on P388 leukemia cells and cytotoxic activity by cytotoxic T lymphocytes on P815 mastocytoma cells (Scheme 7) 96 . Furthermore, a hyper acid-sensitive Sieber amide resin was used for the synthesis of MDP and spacer modified MDP 4 .…”

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

“…2). MDP derivative 20 showed a substantial amount of IL-8 production, confirming that the β-azidopropanol modification on the anomeric position is allowed [43–44]. Of conjugates 2 – 5 the conjugates 2 and 3 showed activity close to background levels.…”