Synthesis and biological evaluation of a new class of vaccine adjuvants: aminoalkyl glucosaminide 4-phosphates (AGPs)

Johnson, David A.; Sowell, C. Gregory; Johnson, Craig; Livesay, Mark T.; Keegan, David S.; Rhodes, Michael J.; Ulrich, J. Terry; Ward, Julian; Cantrell, John L.; Brookshire, Valerie G.

doi:10.1016/s0960-894x(99)00374-1

Cited by 66 publications

(60 citation statements)

References 17 publications

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“…The synthesis of CRX-526 and other AGP has been described previously (19,22). Briefly, the AGP were prepared by a highly convergent method, which allowed chemical differentiation of the hydroxyl and amino groups and sequential introduction of the (R)-3-n-alkanoyloxytetrahexanoyl residues.…”

Section: Crx-526 Crx-567 Crx-568 and Crx-570mentioning

confidence: 99%

A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

Fort

Mozaffarian

Stöver

et al. 2005

The Journal of Immunology

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Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-α release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.

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Section: Crx-526 Crx-567 Crx-568 and Crx-570mentioning

confidence: 99%

A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

Fort

Mozaffarian

Stöver

et al. 2005

The Journal of Immunology

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205

147

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“…MPL TM , also known as AS04, has recently been approved for use in Europe and is defined as 3-O-desacyl-4'-monophosphoryl lipid A, obtained by mild hydrolytic treatment and purification of Salmonella minnesota R595 LPS, and absorbed on aluminum hydroxide or aluminum phosphate. 46,47 The potent adjuvanticity and good safety profile of MPLA has spawned a large number of synthetic lipid A mimics including a new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs) 48,49 such as Corixa's (now GlaxoSmithKline) Ribi 529, [50][51][52] and Eisai's E6020 (Fig. 2).…”

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Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…We report here the results of in vivo structure-function studies of a family of synthetic lipid A mimetics, the aminoalkyl glucosaminide phosphates (AGPs) (13,14). Intravenous or intranasal/intrapulmonary administration of AGPs was evaluated in standardized murine models of nonspecific resistance to bacterial and viral challenges.…”

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Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge

et al. 2005

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A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.The toll-like receptors (TLRs) comprise an evolutionarily conserved receptor family that is capable of detecting and responding to microbial challenge (1). The TLRs recognize a variety of pathogen-specific components, including lipopolysaccharide (LPS), CpG DNA, and microbial membrane and cell wall components (20). Toll-like receptor 4 (TLR4) is critical for the recognition of LPS (30, 31), and considerable progress has recently been made in understanding the interaction of TLR4 with critical accessory molecules implicated in LPS recognition (8,9,17,21,22, 32,40,41). In this regard, it appears that LPS binding protein (LBP) promotes the binding of LPS to CD14, which in turn facilitates the association of the lipid A component of LPS with MD-2 to form a soluble complex that serves as an activating ligand for TLR4 on the cell surface. Binding of the MD-2/LPS complex to TLR4 results in the aggregation of TLR4 into lipid rafts and the activation of several distinct intracellular signaling pathways that results in increased transcription of many genes encoding cytokines, defensins, chemokines, and alpha/beta interferons (28, 38). These effector molecules determine a wide range of biological activities, including further production of cytokines, enhancement of microbicidal activity of phagocytic cells, and migration/maturation of dendritic cells (5,23,36).Before the discovery that LPS interacts with TLR4, evidence demonstrating the importance of innate immune activation in controlling infection with gram-neg...

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Synthesis and biological evaluation of a new class of vaccine adjuvants: aminoalkyl glucosaminide 4-phosphates (AGPs)

Cited by 66 publications

References 17 publications

A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

Potential adjuvantic properties of innate immune stimuli

Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge

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