Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Toll-like Receptor Agonist Conjugation: A Chemical Perspective.

ABSTRACT: Toll-like receptors (TLRs) are vital elements of the mammalian immune system that function by recognizing pathogen-associated molecular patterns (PAMPs), bridging innate and adaptive immunity. They have become a prominent therapeutic target for the treatment of infectious diseases, cancer, and allergies, with many TLR agonists currently in clinical trials or approved as immunostimulants. Numerous studies have shown that conjugation of TLR agonists to other molecules can beneficially influence their potency, toxicity, pharmacokinetics, or function. The functional properties of TLR agonist conjugates, however, are highly dependent on the ligation strategy employed. Here, we review the chemical structural requirements for effective functional TLR agonist conjugation. In addition, we provide similar analysis for those that have yet to be conjugated. Moreover, we discuss applications of covalent TLR agonist conjugation and their implications for clinical use.

SUBMITTER: Ignacio BJ

PROVIDER: S-EPMC10642707 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Toll-like Receptor Agonist Conjugation: A Chemical Perspective.

Ignacio Bob J BJ Albin Tyler J TJ Esser-Kahn Aaron P AP Verdoes Martijn M

Bioconjugate chemistry 20180216 3

Toll-like receptors (TLRs) are vital elements of the mammalian immune system that function by recognizing pathogen-associated molecular patterns (PAMPs), bridging innate and adaptive immunity. They have become a prominent therapeutic target for the treatment of infectious diseases, cancer, and allergies, with many TLR agonists currently in clinical trials or approved as immunostimulants. Numerous studies have shown that conjugation of TLR agonists to other molecules can beneficially influence th ...[more]

PMID: 29378134

Similar Datasets

Conjugation of a Toll-Like Receptor Agonist to Glycans of an HIV Native-Like Envelope Trimer Preserves Neutralization Epitopes.

Project description:Small molecule adjuvants are attractive for enhancing broad protection and durability of immune responses elicited by subunit vaccines. Covalent attachment of an adjuvant to an immunogen is particularly attractive because it simultaneously delivers both entities to antigen presenting cells resulting in more efficient immune activation. There is, however, a lack of methods to conjugate small molecule immune potentiators to viral glycoprotein immunogens without compromising epitope integrity. We describe herein a one-step enzymatic conjugation approach for the covalent attachment of small molecule adjuvants to N-linked glycans of viral glycoproteins. It involves the attachment of an immune potentiator to CMP-Neu5AcN3 by Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition followed by sialyltransferase-mediated transfer to N-glycans of a viral glycoprotein. The method was employed to modify a native-like HIV envelope trimer with a Toll-like receptor 7/8 agonist. The modification did not compromise Env-trimer recognition by several broadly neutralization antibodies. Electron microscopy confirmed structural integrity of the modified immunogen.

| S-EPMC9510654 | biostudies-literature

The toll-like receptor agonist imiquimod is active against prions.

Project description:Using a yeast-based assay, a previously unsuspected antiprion activity was found for imiquimod (IQ), a potent Toll-like receptor 7 (TLR7) agonist already used for clinical applications. The antiprion activity of IQ was first detected against yeast prions [PSI (+) ] and [URE3], and then against mammalian prion both ex vivo in a cell-based assay and in vivo in a transgenic mouse model for prion diseases. In order to facilitate structure-activity relationship studies, we conducted a new synthetic pathway which provides a more efficient means of producing new IQ chemical derivatives, the activity of which was tested against both yeast and mammalian prions. The comparable antiprion activity of IQ and its chemical derivatives in the above life forms further emphasizes the conservation of prion controlling mechanisms throughout evolution. Interestingly, this study also demonstrated that the antiprion activity of IQ and IQ-derived compounds is independent from their ability to stimulate TLRs. Furthermore, we found that IQ and its active chemical derivatives inhibit the protein folding activity of the ribosome (PFAR) in vitro.

| S-EPMC3745460 | biostudies-literature

The Toll-like receptor 7 agonist imiquimod increases ethanol self-administration and induces expression of Toll-like receptor related genes.

Project description:There is growing evidence that immune signalling may be involved in both the causes and consequences of alcohol abuse. Toll-like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption. We administered the TLR7-specific agonist imiquimod in male and female Long-Evans rats to determine (1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and (2) whether TLR7 activation could modulate operant alcohol self-administration. Interferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2- and 24-h post-injection regardless of alcohol history and TLR3 and 7 gene expression was increased as well. The proinflammatory cytokine TNFα was increased 24-h post-injection in rats with an alcohol self-administration history, but this effect did not persist after four injections, suggesting molecular tolerance. Ethanol consumption was increased 24 h after imiquimod injections but did not occur until the third injection, suggesting adaptation to repeated TLR7 activation is necessary for increased drinking to occur. Notably, imiquimod reliably induced weight loss, indicating that sickness behaviour persisted across repeated injections. These findings show that TLR7 activation can modulate alcohol drinking in an operant self-administration paradigm and suggest that TLR7 and IRF7 signalling pathways may be a viable druggable target for treatment of AUD.

| S-EPMC9286850 | biostudies-literature

Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist.

Project description:In response to ligand binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation-2 (MD-2) receptor complex, two major signaling pathways are activated that involve different adaptor proteins. One pathway depends on myeloid differentiation marker 88 (MyD88), which elicits proinflammatory responses, whereas the other depends on Toll-IL-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF), which elicits type I interferon production. Here, we showed that the TLR4 agonist and vaccine adjuvant CRX-547, a member of the aminoalkyl glucosaminide 4-phosphate (AGP) class of synthetic lipid A mimetics, displayed TRIF-selective signaling in human cells, which was dependent on a minor structural modification to the carboxyl bioisostere corresponding to the 1-phosphate group on most lipid A types. CRX-547 stimulated little or no activation of MyD88-dependent signaling molecules or cytokines, whereas its ability to activate the TRIF-dependent pathway was similar to that of a structurally related inflammatory AGP and of lipopolysaccharide from Salmonella minnesota. This TRIF-selective signaling response resulted in the production of substantially less of the proinflammatory mediators that are associated with MyD88 signaling, thereby potentially reducing toxicity and improving the therapeutic index of this synthetic TLR4 agonist and vaccine adjuvant.

| S-EPMC3684200 | biostudies-literature

Micellization of Lipopeptides Containing Toll-like Receptor Agonist and Integrin Binding Sequences.

Project description:Short bioactive peptide sequences are of great interest in biomaterials development. We investigate the self-assembly of a lipopeptide containing both the highly cationic CSK4 toll-like receptor agonist hexapeptide sequence and RGDS integrin-binding motif, i.e., C16-CSK4RGDS, as well as the control containing a scrambled terminal sequence C16-CSK4GRDS. Both lipopeptides are found to form micelles, as revealed by small-angle X-ray scattering and cryogenic transmission electron microscopy, and modeled using atomistic molecular dynamics simulations. We carefully examined methods to probe the aggregation of the molecules, i.e. to obtain the critical micelle concentration (CMC). Fluorescent probe assays using 1-anilino-8-naphthalenesulfonate (ANS) reveal low CMC values, 1-2 μM, which contrast with consistent values more than 2 orders of magnitude larger obtained from surface tension and electrical conductivity as well as unexpected UV/vis absorption spectra discontinuities and fluoresccence probe assays using Nile red. The anomalous results obtained from an ANS fluorescence probe are ascribed to the effect of ANS binding to the cationic (lysine and arginine) residues in the lipopeptide, which leads to a conformational change, as shown by circular dichroism, even at low concentrations below the actual CMC. Despite the small change in the peptide sequence (swapping of G and R residues), there is surprisingly a significant difference in the aggregation propensity and association number, both of which are greater for C16-CSK4GRDS. Both lipopeptides are cytocompatible (with fibroblasts and myoblasts) at low concentration, although cytotoxicity is noted at higher concentration.

| S-EPMC11660038 | biostudies-literature

Activation of dendritic cells by the novel Toll-like receptor 3 agonist RGC100.

Project description:Toll-like receptor (TLR) 3 agonists emerged as attractive candidates for vaccination strategies against tumors and pathogens. An important mechanism of action of such agonists is based on the activation of TLR3-expressing dendritic cells (DCs), which display a unique capacity to induce and stimulate T-cell responses. In this context, it has been demonstrated that targeting of TLR3 by double-stranded RNA such as poly(I:C) results in potent activation of DCs. Major disadvantages of poly(I:C) comprise its undefined chemical structure and very poor homogeneity, with subsequent unpredictable pharmacokinetics and high toxicity. In the present study, we evaluated the physicochemical properties and biological activity of the novel TLR3 agonist RGC100. RGC100 has a defined chemical structure, with a defined length (100 bp) and molecular weight (64.9 KDa) and a good solubility. RGC100 is stable in serum and activates myeloid DCs through TLR3 targeting, as evidenced by gene silencing experiments. Activation of mouse and human myeloid CD1c(+) DCs by RGC100 leads to secretion of several proinflammatory cytokines. In addition, RGC100 improves the ability of CD1c(+) DCs to stimulate T-cell proliferation. Due to its physicochemical properties and its immunostimulatory properties, RGC100 may represent a promising adjuvant for prophylactic and therapeutic vaccination strategies.

| S-EPMC3878805 | biostudies-literature

A toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages.

Project description:Switching macrophages from a pro-tumor type to an anti-tumor state is a promising strategy for cancer immunotherapy. Existing agents, many derived from bacterial components, have safety or specificity concerns. Here, we postulate that the structures of the bacterial signals can be mimicked by using non-toxic biomolecules of simple design. Based on bioactivity screening, we devise a glucomannan polysaccharide with acetyl modification at a degree of 1.8 (acGM-1.8), which specifically activates toll-like receptor 2 (TLR2) signaling and consequently induces macrophages into an anti-tumor phenotype. For acGM-1.8, the degree of acetyl modification, glucomannan pattern, and acetylation-induced assembly are three crucial factors for its bioactivity. In mice, intratumoral injection of acGM-1.8 suppresses the growth of two tumor models, and this polysaccharide demonstrates higher safety than four classical TLR agonists. In summary, we report the design of a new, safe, and specific TLR2 agonist that can generate macrophages with strong anti-tumor potential in mice.

| S-EPMC6531447 | biostudies-literature

Flagellin a toll-like receptor 5 agonist as an adjuvant in chicken vaccines.

Project description:Chicken raised under commercial conditions are vulnerable to environmental exposure to a number of pathogens. Therefore, regular vaccination of the flock is an absolute requirement to prevent the occurrence of infectious diseases. To combat infectious diseases, vaccines require inclusion of effective adjuvants that promote enhanced protection and do not cause any undesired adverse reaction when administered to birds along with the vaccine. With this perspective in mind, there is an increased need for effective better vaccine adjuvants. Efforts are being made to enhance vaccine efficacy by the use of suitable adjuvants, particularly Toll-like receptor (TLR)-based adjuvants. TLRs are among the types of pattern recognition receptors (PRRs) that recognize conserved pathogen molecules. A number of studies have documented the effectiveness of flagellin as an adjuvant as well as its ability to promote cytokine production by a range of innate immune cells. This minireview summarizes our current understanding of flagellin action, its role in inducing cytokine response in chicken cells, and the potential use of flagellin as well as its combination with other TLR ligands as an adjuvant in chicken vaccines.

| S-EPMC3957660 | biostudies-literature

The Toll-like receptor-3 agonist polyinosinic:polycytidylic acid triggers nigrostriatal dopaminergic degeneration.

Project description:In Parkinson's disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with glial reactions. Such inflammatory processes are commonly considered an epiphenomenon of neuronal degeneration. However, there is increasing recognition of the role of neuroinflammation as an initiation factor of DA neuron degeneration. To investigate this issue, we established a new model of brain inflammation by injecting the Toll-like receptor 3 (TLR-3) agonist polyinosinic:polycytidylic acid [poly(I:C)] in the SN of adult rats. Poly(I:C) injection induced a sustained inflammatory reaction in the SN and in the dorsolateral striatum. Significant changes were detected in proteins relevant to synaptic transmission and axonal transport. In addition, cytoplasmic mislocalization of neuronal TAR DNA binding protein TDP-43 was observed. Poly(I:C) injection increased the susceptibility of midbrain DA neurons to a subsequent neurotoxic trigger (low-dose 6-hydroxydopamine). Systemic delivery of interleukin-1 receptor antagonist protected SN DA neurons exposed to combined poly(I:C) induced inflammatory and neurotoxic oxidative stress. These data indicate that viral-like neuroinflammation induces predegenerative changes in the DA system, which lowers the set point toward neuronal dysfunction and degeneration. New powerful neuroprotective therapies for PD might be considered by targeting critical inflammatory mechanisms, including cytokine-induced neurotoxicity.

| S-EPMC3075577 | biostudies-literature

Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist.

Project description:Previous work demonstrated that pre-exposure to ozone primes innate immunity and increases Toll-like receptor-4 (TLR4)-mediated responses to subsequent stimulation with LPS. To explore the pulmonary innate immune response to ozone exposure further, we investigated the effects of ozone in combination with Pam3CYS, a synthetic TLR2/TLR1 agonist. Whole-lung lavage (WLL) and lung tissue were harvested from C57BL/6 mice after exposure to ozone or filtered air, followed by saline or Pam3CYS 24 hours later. Cells and cytokines in the WLL, the surface expression of TLRs on macrophages, and lung RNA genomic expression profiles were examined. We demonstrated an increased WLL cell influx, increased IL-6 and chemokine KC (Cxcl1), and decreased macrophage inflammatory protein (MIP)-1? and TNF-? in response to Pam3CYS as a result of ozone pre-exposure. We also observed the increased cell surface expression of TLR4, TLR2, and TLR1 on macrophages as a result of ozone alone or in combination with Pam3CYS. Gene expression analysis of lung tissue revealed a significant increase in the expression of genes related to injury repair and the cell cycle as a result of ozone alone or in combination with Pam3CYS. Our results extend previous findings with ozone/LPS to other TLR ligands, and suggest that the ozone priming of innate immunity is a general mechanism. Gene expression profiling of lung tissue identified transcriptional networks and genes that contribute to the priming of innate immunity at the molecular level.

| S-EPMC3547086 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data