Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Borio, A; Holgado, A; Passegger, C; Strobl, H; Beyaert, R; Heine, H; Zamyatina, A.
Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid A Mimicking Glycolipids.
Molecules. 2023; 28(16): 5948 Doi: 10.3390/molecules28165948 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Co-authors Med Uni Graz

Passegger Christina Angelika

Strobl Herbert

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Abstract:

The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex is a key receptor of the innate immune system and a major driver of inflammation that is responsible for the multifaceted defense response to Gram-negative infections. However, dysfunction in the tightly regulated mechanisms of TLR4-mediated signaling leads to the uncontrolled upregulation of local and systemic inflammation, often resulting in acute or chronic disease. Therefore, the TLR4/MD-2 receptor complex is an attractive target for the design and development of anti-inflammatory therapies which aim to control the unrestrained activation of TLR4-mediated signaling. Complex structure-activity relationships and species-specificity behind ligand recognition by the TLR4/MD-2 complex complicate the development of MD-2-specific TLR4 antagonists. The restriction of the conformational flexibility of the disaccharide polar head group is one of the key structural features of the newly developed lipid A-mimicking glycophospholipids, which are potential inhibitors of TLR4-mediated inflammation. Since phosphorylation has a crucial influence on MD-2-ligand interaction, glycolipids with variable numbers and positioning of phosphate groups were synthesized and evaluated for their ability to inhibit TLR4-mediated pro-inflammatory signaling in human and murine immune cells. A bis-phosphorylated glycolipid was found to have nanomolar antagonist activity on human TLR4 while acting as a partial agonist on murine TLR4. The glycolipid inhibited mTLR4/MD-2-mediated cytokine release, acting as an antagonist in the presence of lipopolysaccharide (LPS), but at the same time induced low-level cytokine production.

Find related publications in this database (using NLM MeSH Indexing)

Humans - administration & dosage

Animals - administration & dosage

Mice - administration & dosage

Lipid A - administration & dosage

Toll-Like Receptor 4 - administration & dosage

Glycolipids - pharmacology

Ligands - administration & dosage

Cell Differentiation - administration & dosage

Cytokines - administration & dosage

Inflammation - administration & dosage

Find related publications in this database (Keywords)

carbohydrate-based inhibitors

lipopolysaccharide

inflammation

Toll-like receptor

carbohydrates

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