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Journal ArticleDOI

Muramyl dipeptide and its derivatives: peptide adjuvant in immunological disorders and cancer therapy.

01 Sep 2011-Current Bioactive Compounds (Curr Bioact Compd)-Vol. 7, Iss: 3, pp 180-197
TL;DR: The structural modifications of MDP and its derivatives have been extensively studied in an attempt to increase adjuvant activity and boost the immune response effectively for clinical use in the treatment of cancer and other diseases.
Abstract: Muramyl dipeptide (MDP) is a synthetic immunoreactive peptide consisting of N-acetyl muramic acid attached to a short amino acid chain of L-Ala-D-isoGln. It was first identified in bacterial cell wall peptidoglycan as an active component in Freund's complete adjuvant. In the cell, MDP is detected by NOD2, a cytoplasmic receptor belonging to the human innate immune system. NOD2 mutations are frequently observed in patients with Crohn's disease, an autoimmune disorder, suggesting the significance of the MDP-NOD2 pathway in activating immunity. For this reason, structural modifications of MDP and its derivatives have been extensively studied in an attempt to increase adjuvant activity and boost the immune response effectively for clinical use in the treatment of cancer and other diseases. This review summarizes the synthetic chemistry of MDP and its derivatives and discusses their pharmacological action and stereoselective synthesis.

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Citations
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Journal ArticleDOI
11 Jul 2014
TL;DR: This review concentrates on recent and relevant studies emphasizing current reports dealing with the most studied antigens and adjuvants, and pertinent examples of vaccines.
Abstract: Liposomes and liposome-derived nanovesicles such as archaeosomes and virosomes have become important carrier systems in vaccine development and the interest for liposome-based vaccines has markedly...

389 citations


Cites background from "Muramyl dipeptide and its derivativ..."

  • ...Numerous MDP derivatives have been synthesized to evaluate their immunostimulatory effects and adjuvant activity [Traub et al. 2006; Ogawa et al. 2011]....

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Journal ArticleDOI
TL;DR: This review presents the sources and mechanisms of anticancer peptides and further discusses modification strategies to improve the anticancer effects of bioactive peptides.

251 citations


Cites background from "Muramyl dipeptide and its derivativ..."

  • ...Bestatin, MDP, and FK-565 are three immunomodulatory peptides with antitumor activities, as shown above [79–81]....

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  • ...PR-39 RRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPPRFPPR antitumor effects, which could be attributed to the release of proinflammatory mediators by the activation of macrophages, NK (natural killer) cells, and lymphocytes [79]....

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Journal ArticleDOI
TL;DR: The mechanisms responsible for the induction of trained immunity are described and strategies to regulate it are proposed as a potential treatment of immune-related diseases.
Abstract: Immunotherapy is revolutionizing the treatment of diseases in which dysregulated immune responses have an important role. However, most of the immunotherapy strategies currently being developed engage the adaptive immune system. In the past decade, both myeloid (monocytes, macrophages and dendritic cells) and lymphoid (natural killer cells and innate lymphoid cells) cell populations of the innate immune system have been shown to display long-term changes in their functional programme through metabolic and epigenetic programming. Such reprogramming causes these cells to be either hyperresponsive or hyporesponsive, resulting in a changed immune response to secondary stimuli. This de facto innate immune memory, which has been termed 'trained immunity', provides a powerful 'targeting framework' to regulate the delicate balance of immune homeostasis, priming, training and tolerance. In this Opinion article, we set out our vision of how to target innate immune cells and regulate trained immunity to achieve long-term therapeutic benefits in a range of immune-related diseases. These include conditions characterized by excessive trained immunity, such as inflammatory and autoimmune disorders, allergies and cardiovascular disease and conditions driven by defective trained immunity, such as cancer and certain infections.

239 citations

Journal ArticleDOI
29 Oct 2020-Cell
TL;DR: It is shown that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

82 citations

Journal ArticleDOI
TL;DR: It is shown that activation of Nod2 by its ligand, muramyl dipeptide in the bacterial cell wall, induces rapid degradation of NOD2, which confers MDP tolerance in vitro and in vivo, which indicates that TLRs and NLRs induce a tolerant state through distinct molecular mechanisms that protect the host from septic shock.

77 citations


Cites background from "Muramyl dipeptide and its derivativ..."

  • ...Nod2, a cytoplasmic NLR, senses the component of bacterial cell wall peptidoglycan called MDP, which consists of N-acetylmuramyl-L-Ala-D-Gln (28)....

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  • ...3 The abbreviations used are: TLR, Toll-like receptor; NLR, nucleotide binding domain (NBD) and leucine-rich repeat (LRR); Nod2, nucleotide-binding oligomerization domain-containing 2; MDP, muramyl dipeptide (N-acetylmuramyl-L-Ala-D-Gln (MDP-LD)); IRAK, interleukin-1 receptor-associated kinase; CARD, caspase recruitment domain; Ub, ubiquitin; iNOS, inducible nitric-oxide synthase; BMDM, bone marrow-derived macrophages; MDPDD, N-acetylmuramyl-D-alanyl-D-isoglutamine; MDP-LL, N-acetylmuramylL-alanyl-L-isoglutamine; 17AAG, 17-allylamino-17-demethoxygeldanamycin; RAD, radicicol; SOCS, suppressor of cytokine signaling; SH2, Src homology 2....

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References
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Journal ArticleDOI
31 May 2001-Nature
TL;DR: It is suggested that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn’s disease that can now be further investigated.
Abstract: Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology A susceptibility locus for Crohn's disease has been mapped to chromosome 16 Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated

5,388 citations

Journal ArticleDOI
TL;DR: No single agent or distinct mechanism is the sine qua non motive that explains all aspects of IBD, and several distinguishing factors are likely necessary to result in either CD or UC; this review will attempt to discuss those that currently appear important.

2,054 citations

Journal ArticleDOI
TL;DR: In several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions, and the different models for the architecture are discussed with respect to structural and physical parameters.
Abstract: The peptidoglycan (murein) sacculus is a unique and essential structural element in the cell wall of most bacteria. Made of glycan strands cross-linked by short peptides, the sacculus forms a closed, bag-shaped structure surrounding the cytoplasmic membrane. There is a high diversity in the composition and sequence of the peptides in the peptidoglycan from different species. Furthermore, in several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions. Limited number of biophysical data on the thickness, elasticity and porosity of peptidoglycan are available. The different models for the architecture of peptidoglycan are discussed with respect to structural and physical parameters.

1,876 citations

Journal ArticleDOI
TL;DR: The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease.
Abstract: The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy.

1,772 citations

Journal ArticleDOI
04 Feb 2005-Science
TL;DR: It is shown that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod1-deficient mice, providing a possible mechanism for Nod 2 mutations in CD.
Abstract: The gene encoding the Nod2 protein is frequently mutated in Crohn's disease (CD) patients, although the physiological function of Nod2 in the intestine remains elusive. Here we show that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. These animals are susceptible to bacterial infection via the oral route but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal anti-microbial peptides, known as cryptdins. The Nod2 protein is thus a critical regulator of bacterial immunity within the intestine, providing a possible mechanism for Nod2 mutations in CD.

1,760 citations

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