Structure-Activity Relationship of Chemically Synthesized Nonreducing Parts of Lipid a Analogs

Jy, Homma; Matsuura, Motohiro; Kumazawa, Yoshio

doi:10.1007/978-1-4757-5140-6_6

Cited by 16 publications

(7 citation statements)

References 5 publications

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“…Specifically, we identified that Gly 69 and Tyr 42 on mMD-2 are required for a full response to lipid IV A . 5 Because Gly 69 and Tyr 42 reside at the opposite surface of the dimerization interface, these residues likely indirectly affect receptor dimerization through affecting the MD-2⅐TLR4 binding angle. Because equine MD-2 has Ser 42 instead of Tyr…”

Section: Discussionmentioning

confidence: 99%

MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation

Meng

Lien²,

Golenbock³

2010

Journal of Biological Chemistry

111

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Section: Discussionmentioning

confidence: 99%

MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation

Meng

Lien²,

Golenbock³

2010

Journal of Biological Chemistry

111

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“…The number and length of the acyl chains determine the agonistic property of lipid A (17)(18)(19). E. coli lipid A is usually hexaacylated and acts as a potent agonist for all mammalian cells.…”

mentioning

confidence: 99%

Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2

Ohto

Fukase

Miyake

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

297

411

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Lipopolysaccharide (LPS), also known as endotoxin, activates the innate immune response through toll-like receptor 4 (TLR4) and its coreceptor, MD-2. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. Tetraacylated lipid IVa, a synthetic lipid A precursor, acts as a weak agonist to mouse TLR4/MD-2, but as an antagonist to human TLR4/MD-2. However, it remains unclear as to how LPS and lipid IVa show agonistic or antagonistic activities in a species-specific manner. The present study reports the crystal structures of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa complexes at 2.5 and 2.7 Å resolutions, respectively. Mouse TLR4/MD-2/LPS exhibited an agonistic "m"-shaped 2:2:2 complex similar to the human TLR4/MD-2/LPS complex. Mouse TLR4/MD-2/lipid IVa complex also showed an agonistic structural feature, exhibiting architecture similar to the 2:2:2 complex. Remarkably, lipid IVa in the mouse TLR4/MD-2 complex occupied nearly the same space as LPS, although lipid IVa lacked the two acyl chains. Human MD-2 binds lipid IVa in an antagonistic manner completely differently from the way mouse MD-2 does. Together, the results provide structural evidence of the agonistic property of lipid IVa on mouse TLR4/MD-2 and deepen understanding of the ligand binding and dimerization mechanism by the structurally diverse LPS variants.

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“…Our results showed that selective removal of 6-O-sulfo groups at C-6 of D-glucosamine decreased its activity. The TLR4-MD-2 receptor complex has affinity with amphiphilic lipid A and its analogs, and is sensitive to the nature and length of acyl chains and the interaction with charged groups on the hydrophilic portion of ligands [46][47][48]. Crystal structures of antagonistic (lipid IVa, Eritoran) binding to TLR4-MD-2 show that di-glucosamine residues do not interact directly with MD-2 whereas lipid chains interact with MD-2 through hydrophobic contacts.…”

Section: Discussionmentioning

confidence: 99%

Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4–NF-κB signaling

Babazada

Yamashita

Yanamoto

et al. 2014

Journal of Controlled Release

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Self-assembling heparin nanoparticles have attracted much attention as promising drug carriers for various drugs, genes and imaging agents. In the present investigation, we found that heparin nanoparticles are selective Toll-like receptor 4 (TLR-4) antagonists and have a much greater anti-inflammatory effect than native heparin. More specifically, we developed self-assembling nanoparticles composed of glycol-split heparin/D-erythro-sphingosine conjugates (NAHNP), characterized their physicochemical properties and anti-inflammatory effect in vitro. Unlike native heparin, NAHNP significantly inhibited lipopolysaccharide-induced activation of MyD88-dependent NF-κB signaling pathway and production of pro-inflammatory cytokines such as TNF-alpha from mouse macrophages with IC50 = 0.019 mg/mL. Furthermore, we investigated the structure-activity relationship of the conjugates and identified the length of attached alkyl chains of d-erythro-sphingosine to be critical for anti-inflammatory effect. Decrease in alkyl chain length of NAHNP resulted in loss of inhibitory activity. In line with these findings, 6-O-sulfate groups of D-glucosamine residue were essential for effective inhibition, while removal of 2-O-sulfo and 3-O-sulfo groups as well as replacement of N-sulfo groups with N-acetyl did not alter anti-inflammatory activity. Therefore, NAHNP would be a promising candidate in acute and chronic inflammatory disorders, in addition to the nature of a drug carrier.

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Structure-Activity Relationship of Chemically Synthesized Nonreducing Parts of Lipid a Analogs

Cited by 16 publications

References 5 publications

MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation

MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation

Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2

Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4–NF-κB signaling

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