Lipid A in Cancer Therapies Preclinical Results

Reisser, D; Jeannin, Jean–François

doi:10.1007/978-1-4419-1603-7_9

Cited by 12 publications

(12 citation statements)

References 43 publications

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“… 4 − 6 Inappropriate regulation of TLR4 signaling and ensuing overactivation of innate immune system was shown to contribute to the development and pathogenesis of chronic inflammatory, autoimmune, and infectious diseases, including asthma, arthritis, multiple sclerosis, inflammatory bowel disease, and cancer. 7 − 10 …”

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confidence: 99%

Conformationally Constrained Lipid A Mimetics for Exploration of Structural Basis of TLR4/MD-2 Activation by Lipopolysaccharide

et al. 2013

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Recognition of the lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, by the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD-2) complex is essential for the control of bacterial infection. A pro-inflammatory signaling cascade is initiated upon binding of membrane-associated portion of LPS, a glycophospholipid Lipid A, by a coreceptor protein MD-2, which results in a protective host innate immune response. However, activation of TLR4 signaling by LPS may lead to the dysregulated immune response resulting in a variety of inflammatory conditions including sepsis syndrome. Understanding of structural requirements for Lipid A endotoxicity would ensure the development of effective anti-inflammatory medications. Herein, we report on design, synthesis, and biological activities of a series of conformationally confined Lipid A mimetics based on β,α-trehalose-type scaffold. Replacement of the flexible three-bond β(1→6) linkage in diglucosamine backbone of Lipid A by a two-bond β,α(1↔1) glycosidic linkage afforded novel potent TLR4 antagonists. Synthetic tetraacylated bisphosphorylated Lipid A mimetics based on a β–GlcN(1↔1)α–GlcN scaffold selectively block the LPS binding site on both human and murine MD-2 and completely abolish lipopolysaccharide-induced pro-inflammatory signaling, thereby serving as antisepsis drug candidates. In contrast to their natural counterpart lipid IVa, conformationally constrained Lipid A mimetics do not activate mouse TLR4. The structural basis for high antagonistic activity of novel Lipid A mimetics was confirmed by molecular dynamics simulation. Our findings suggest that besides the chemical structure, also the three-dimensional arrangement of the diglucosamine backbone of MD-2-bound Lipid A determines endotoxic effects on TLR4.

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confidence: 99%

Conformationally Constrained Lipid A Mimetics for Exploration of Structural Basis of TLR4/MD-2 Activation by Lipopolysaccharide

et al. 2013

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“…However, adjunct treatment per se, unlike cidofovir, did not activate NK cells and triggered differentiation of B cells into antibody-secreting plasma cells. Aluminum hydroxide and MPL are mostly used as adjuvants in cancer vaccines though various lipids A have been used to treat animals with established tumors [ 65 ]. In animal models, the antitumor effect of LPS (lipopolysaccharide) and of the biologically active moiety, lipid A, was shown to be indirect and to rely on the induction of both an innate and specific immune response, leading to cytokine production [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of tumor-tumor interactions in a double human cervical carcinoma xenograft model in nude mice

et al. 2018

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Tumor-tumor distant interactions within one organism are of major clinical relevance determining clinical outcome. To investigate this poorly understood phenomenon, a double human cervical xenograft model in nude mice was developed. A first tumor was induced subcutaneously by injection of human papillomavirus positive cervical carcinoma cells into the mouse lower right flank and 3 weeks later, animals were challenged with the same tumor cell line injected subcutaneously into the upper left flank. These tumors had no direct physical contact and we found no systemic changes induced by the primary tumor affecting the growth of a secondary tumor. However, ablation of the primary tumor by local treatment with cidofovir, a nucleotide analogue with known antiviral and antiproliferative properties, resulted not only in a local antitumor effect but also in a temporary far-reaching effect leading to retarded growth of the challenged tumor. Cidofovir far-reaching effects were linked to a reduced tumor-driven inflammation, to increased anti-tumor immune responses, and could not be enhanced by co-administration with immune stimulating adjuvants. Our findings point to the potential use of cidofovir in novel therapeutic strategies aiming to kill tumor cells as well as to influence the immune system to fight cancer.

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“…A number of studies also suggested a possible implication of TLR4 in cardiovascular disorders [ 54 ] and Alzheimer desease – associated pathology [ 55 ]. Therapeutic down-regulation of the TLR4 signaling is believed to be beneficial for treatment of numerous chronic and acute inflammatory diseases such as asthma [ 51 ], arthritis [ 52 ], influenza [ 50 ], and cancer [ 56 ]. Furthermore, TLR4 has been shown to link the innate and adaptive immunity [ 57 – 58 ], underscoring stimulation of the TLR4·MD-2 complex by non-toxic TLR4-specific ligands as an apparent tactic for development of novel vaccine adjuvants [ 59 – 61 ].…”

Section: Introductionmentioning

confidence: 99%

Aminosugar-based immunomodulator lipid A: synthetic approaches

Zamyatina

2018

Beilstein J. Org. Chem.

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The immediate immune response to infection by Gram-negative bacteria depends on the structure of a lipopolysaccharide (LPS, also known as endotoxin), a complex glycolipid constituting the outer leaflet of the bacterial outer membrane. Recognition of picomolar quantities of pathogenic LPS by the germ-line encoded Toll-like Receptor 4 (TLR4) complex triggers the intracellular pro-inflammatory signaling cascade leading to the expression of cytokines, chemokines, prostaglandins and reactive oxygen species which manifest an acute inflammatory response to infection. The “endotoxic principle” of LPS resides in its amphiphilic membrane-bound fragment glycophospholipid lipid A which directly binds to the TLR4·MD-2 receptor complex. The lipid A content of LPS comprises a complex mixture of structural homologs varying in the acylation pattern, the length of the (R)-3-hydroxyacyl- and (R)-3-acyloxyacyl long-chain residues and in the phosphorylation status of the β(1→6)-linked diglucosamine backbone. The structural heterogeneity of the lipid A isolates obtained from bacterial cultures as well as possible contamination with other pro-inflammatory bacterial components makes it difficult to obtain unambiguous immunobiological data correlating specific structural features of lipid A with its endotoxic activity. Advanced understanding of the therapeutic significance of the TLR4-mediated modulation of the innate immune signaling and the central role of lipid A in the recognition of LPS by the innate immune system has led to a demand for well-defined materials for biological studies. Since effective synthetic chemistry is a prerequisite for the availability of homogeneous structurally distinct lipid A, the development of divergent and reproducible approaches for the synthesis of various types of lipid A has become a subject of considerable importance. This review focuses on recent advances in synthetic methodologies toward LPS substructures comprising lipid A and describes the synthesis and immunobiological properties of representative lipid A variants corresponding to different bacterial species. The main criteria for the choice of orthogonal protecting groups for hydroxyl and amino functions of synthetically assembled β(1→6)-linked diglucosamine backbone of lipid A which allows for a stepwise introduction of multiple functional groups into the molecule are discussed. Thorough consideration is also given to the synthesis of 1,1′-glycosyl phosphodiesters comprising partial structures of 4-amino-4-deoxy-β-L-arabinose modified Burkholderia lipid A and galactosamine-modified Francisella lipid A. Particular emphasis is put on the stereoselective construction of binary glycosyl phosphodiester fragments connecting the anomeric centers of two aminosugars as well as on the advanced P(III)-phosphorus chemistry behind the assembly of zwitterionic double glycosyl phosphodiesters.

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Lipid A in Cancer Therapies Preclinical Results

Cited by 12 publications

References 43 publications

Conformationally Constrained Lipid A Mimetics for Exploration of Structural Basis of TLR4/MD-2 Activation by Lipopolysaccharide

Conformationally Constrained Lipid A Mimetics for Exploration of Structural Basis of TLR4/MD-2 Activation by Lipopolysaccharide

Investigation of tumor-tumor interactions in a double human cervical carcinoma xenograft model in nude mice

Aminosugar-based immunomodulator lipid A: synthetic approaches

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