Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw 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
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- Co-Autor*innen der 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