Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid A Mimicking Glycolipids

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