Advanced search
1 file | 5.63 MB Add to list

Structure-activity relationship in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists

(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(7). p.2895-2909
Author
Organization
Abstract
The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds.
Keywords
N-LINKED GLYCOSYLATIONS, LIPID-A ANALOGS, SEVERE SEPSIS, CELL, ACTIVATION, LIPOPOLYSACCHARIDE RECOGNITION, BIOLOGICAL-ACTIVITY, MD-2, ENDOTOXIN, PROTEIN, BIOACTIVITY

Downloads

  • 3022 18Facchini.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 5.63 MB

Citation

Please use this url to cite or link to this publication:

MLA
Facchini, Fabio A et al. “Structure-activity Relationship in Monosaccharide-based Toll-like Receptor 4 (TLR4) Antagonists.” JOURNAL OF MEDICINAL CHEMISTRY 61.7 (2018): 2895–2909. Print.
APA
Facchini, F. A., Zaffaroni, L., Minotti, A., Rapisarda, S., Calabrese, V., Forcella, M., Fusi, P., et al. (2018). Structure-activity relationship in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists. JOURNAL OF MEDICINAL CHEMISTRY, 61(7), 2895–2909.
Chicago author-date
Facchini, Fabio A, Lenny Zaffaroni, Alberto Minotti, Silvia Rapisarda, Valentina Calabrese, Matilde Forcella, Paola Fusi, et al. 2018. “Structure-activity Relationship in Monosaccharide-based Toll-like Receptor 4 (TLR4) Antagonists.” Journal of Medicinal Chemistry 61 (7): 2895–2909.
Chicago author-date (all authors)
Facchini, Fabio A, Lenny Zaffaroni, Alberto Minotti, Silvia Rapisarda, Valentina Calabrese, Matilde Forcella, Paola Fusi, Cristina Airoldi, Carlotta Ciaramelli, Jean-Marc Billod, Andra B Schromm, Harald Braun, Charys Palmer, Rudi Beyaert, Fabio Lapenta, Roman Jerala, Grisha Pirianov, Sonsoles Martin-Santamaria, and Francesco Peri. 2018. “Structure-activity Relationship in Monosaccharide-based Toll-like Receptor 4 (TLR4) Antagonists.” Journal of Medicinal Chemistry 61 (7): 2895–2909.
Vancouver
1.
Facchini FA, Zaffaroni L, Minotti A, Rapisarda S, Calabrese V, Forcella M, et al. Structure-activity relationship in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(7):2895–909.
IEEE
[1]
F. A. Facchini et al., “Structure-activity relationship in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists,” JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 7, pp. 2895–2909, 2018.
@article{8562978,
  abstract     = {The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds.},
  author       = {Facchini, Fabio A and Zaffaroni, Lenny and Minotti, Alberto and Rapisarda, Silvia and Calabrese, Valentina and Forcella, Matilde and Fusi, Paola and Airoldi, Cristina and Ciaramelli, Carlotta and Billod, Jean-Marc and Schromm, Andra B and Braun, Harald and Palmer, Charys and Beyaert, Rudi and Lapenta, Fabio and Jerala, Roman and Pirianov, Grisha and Martin-Santamaria, Sonsoles and Peri, Francesco},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keywords     = {N-LINKED GLYCOSYLATIONS,LIPID-A ANALOGS,SEVERE SEPSIS,CELL,ACTIVATION,LIPOPOLYSACCHARIDE RECOGNITION,BIOLOGICAL-ACTIVITY,MD-2,ENDOTOXIN,PROTEIN,BIOACTIVITY},
  language     = {eng},
  number       = {7},
  pages        = {2895--2909},
  title        = {Structure-activity relationship in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.7b01803},
  volume       = {61},
  year         = {2018},
}

Altmetric
View in Altmetric
Web of Science
Times cited: