Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529

Baldridge, Jory R.; Cluff, C W; Evans, Jay T.; Lacy, Michael J.; Stephens, Jeffrey R.; Brookshire, Valerie G.; Wang, Rong; Ward, Julian; Yorgensen, Yvonne M.; Persing, David H.; Johnson, David A.

doi:10.1177/09680519020080061501

Cited by 27 publications

(17 citation statements)

References 7 publications

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“…Early observations of the enhanced vaccine response obtained with gram negative bacteria were followed by refinements in this approach using endotoxin, lipid A, MPL or synthetic analogues such as RC529 [86][87][88]. Additionally, MPL was approved in combination with alum (AS04) as adjuvant in two prophylactics vaccines [89].…”

Section: Lps Is a Natural Adjuvant And Its Derivative Monophosphorylmentioning

confidence: 97%

On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives

Pellegrino

Clementi

Radice

2015

Autoimmunity Reviews

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Section: Lps Is a Natural Adjuvant And Its Derivative Monophosphorylmentioning

confidence: 97%

On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives

Pellegrino

Clementi

Radice

2015

Autoimmunity Reviews

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“…Two AGPs were previously reported to induce protective innate immune responses when administered prior to bacterial or viral challenge in mice, though neither the structural features responsible for this activity nor its dependence on TLR4 were described (3). In this study, structural variants of these compounds were used to investigate the TLR requirement and the structure-activity relationship of lipid A-mediated induction of enhanced innate resistance to infectious challenge.…”

Section: Vol 73 2005 Evaluation Of Novel Synthetic Tlr4 Ligands 3049mentioning

confidence: 99%

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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“…Red blood cells were then removed by adding 1 mL per spleen of ACK lysis buffer (0.15 M NH 4 Cl, 10 mM KHCO 3 , 10 mM Na 2 EDTA, pH 7.2). Murine splenocytes were seeded in 48-well plates (5 Â 10 6 cells/mL) in RPMI 1680 medium supplemented with non-essential aa, Sodium Pyruvate, Penicillin-Streptomycin (Lonza) and 1% serum from either WT or CD14-deficient mice.…”

Section: Splenocyte Isolation and Stimulationmentioning

confidence: 99%

“…Aminoalkyl glucosaminide phosphates lipid A mimetics are currently developed as synthetic Toll-like receptor 4 (TLR4) agonists with possible applications as vaccine adjuvants or standalone immunostimulants [1][2][3][4]. The hexa-acylate compound CRX-527, composed of three myristic and three decanoic acyl chains, has been described as one of the most powerful members of this aminoalkyl glucosaminide 4-phosphate family [5].…”

Section: Introductionmentioning

confidence: 99%

CD14‐independent responses induced by a synthetic lipid A mimetic

et al. 2010

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CRX-527 belongs to a new family of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates, which are considered as potential vaccine adjuvants or standalone immunotherapeutics to harness innate immune defenses. Since natural lipid A from bacterial LPS depends on membrane-bound (mCD14) or soluble CD14 for its TLR4 ligand activity, we investigated the involvement of both forms of CD14 in the responses elicited by CRX-527. First, we found that CRX-527 induces NF-jB and interferon regulatory factor-3 (IRF-3) activation in human embryonic kidney cells transfected with TLR4 and MD-2 genes alone, whereas the responses to LPS require either co-transfection of the gene encoding mCD14 or addition of soluble CD14. We then observed that monocyte-derived DC, which are devoid of mCD14 respond to CRX-527 but not to LPS in serum-free medium. Furthermore, we found that, in contrast to LPS, CRX-527 induces the production of cytokines in whole blood of a patient with paroxysmal nocturnal hemoglobinuria, a disease in which mCD14-dependent responses are defective. Finally, we demonstrated that splenocytes from CD14-deficient mice produce cytokines in response to CRX-527 but not to LPS. We conclude that the lipid A mimetic CRX-527 does not require the CD14 co-receptor to elicit TLR4-mediated responses.Key words: CD14 . Lipid A . TLR4 Supporting Information available online IntroductionAminoalkyl glucosaminide phosphates lipid A mimetics are currently developed as synthetic Toll-like receptor 4 (TLR4) agonists with possible applications as vaccine adjuvants or standalone immunostimulants [1][2][3][4]. The hexa-acylate compound CRX-527, composed of three myristic and three decanoic acyl chains, has been described as one of the most powerful members of this aminoalkyl glucosaminide 4-phosphate family [5]. CD14, a GPI-anchored protein expressed at the surface of phagocytes, has been shown to be involved in the induction of TLR4-mediated responses by bacterial LPS [6,7]. Indeed, LPS was shown to bind the LPS binding protein facilitating its transfer to membranebound CD14 (mCD14), which allows LPS to engage TLR4 associated with MD-2 [6]. There is evidence that CD14 is especially important for TLR4 response mediated by the TRIF adaptor molecule, which culminates in activation of the transcription factor interferon regulatory factor-3 (IRF3) required for the production of type I interferon [8]. Cells which express TLR4 but not mCD14, such as endothelial cells and monocytederived DC (MoDC), can use the soluble form of CD14 (sCD14) to mount TLR4-mediated responses to LPS [9]. sCD14 was recently shown to discriminate slight structural differences between distinct TLR4 ligands [10]. The present study was therefore SHORT COMMUNICATION Results and discussionExpression of TLR4 and MD-2 is sufficient for the induction of NF-jB and IRF3 activities by CRX-527In preliminary experiments using transfected human embryonic kidney (HEK) cells expressing different TLR receptors, we confirmed that CRX-527 is a TLR4 agonist devoid of activity o...

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Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529

Cited by 27 publications

References 7 publications

On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives

On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives

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

CD14‐independent responses induced by a synthetic lipid A mimetic

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