Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)- and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling

Sestito, Stefania E.; Facchini, Fabio A.; Morbioli, Ilaria; Billod, Jean-Marc; Martín‐Santamaría, Sonsoles; Casnati, Alessandro; Sansone, Francesco; Peri, Francesco

doi:10.1021/acs.jmedchem.7b00095

Cited by 29 publications

(24 citation statements)

References 55 publications

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“…protruding loop mentioned in the docking study above) or by disturbing the complex stability. In addition, Phe126 remains in its open conformation all along the simulation (Figure S4 in Supplementary Material), this stability was previously associated with antagonist ligands ( 51 ).…”

Section: Resultssupporting

confidence: 57%

Bradyrhizobium Lipid A: Immunological Properties and Molecular Basis of Its Binding to the Myeloid Differentiation Protein-2/Toll-Like Receptor 4 Complex

et al. 2018

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Lipopolysaccharides (LPS) are potent activator of the innate immune response through the binding to the myeloid differentiation protein-2 (MD-2)/toll-like receptor 4 (TLR4) receptor complexes. Although a variety of LPSs have been characterized so far, a detailed molecular description of the structure–activity relationship of the lipid A part has yet to be clarified. Photosynthetic Bradyrhizobium strains, symbiont of Aeschynomene legumes, express distinctive LPSs bearing very long-chain fatty acids with a hopanoid moiety covalently linked to the lipid A region. Here, we investigated the immunological properties of LPSs isolated from Bradyrhizobium strains on both murine and human immune systems. We found that they exhibit a weak agonistic activity and, more interestingly, a potent inhibitory effect on MD-2/TLR4 activation exerted by toxic enterobacterial LPSs. By applying computational modeling techniques, we also furnished a plausible explanation for the Bradyrhizobium LPS inhibitory activity at atomic level, revealing that its uncommon lipid A chemical features could impair the proper formation of the receptorial complex, and/or has a destabilizing effect on the pre-assembled complex itself.

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Section: Resultssupporting

confidence: 57%

Bradyrhizobium Lipid A: Immunological Properties and Molecular Basis of Its Binding to the Myeloid Differentiation Protein-2/Toll-Like Receptor 4 Complex

et al. 2018

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“…This is important as the majority of biological activities are closely associated with different immune-related diseases. TLR4 was the earliest TLR to be identified and is able to combine with PAMPs including LPS, mannose, tuberculosis and mycobacterium tuberculosis, as well as endogenous ligands (30). LPS is a common type of ligand (31).…”

Section: Discussionmentioning

confidence: 99%

Effects of Tim-3 silencing on the viability of fibroblast-like synoviocytes and lipopolysaccharide-induced inflammatory reactions

Long

Chen

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The objective of the present study was to investigate the effects of Tim-3 silencing on cell viability and lipopolysaccharide (LPS)-induced inflammatory reactions in fibroblast-like synoviocytes (FLS). T-cell immunoglobulin mucin domain molecule (Tim)-3 expression in FLS obtained from patients with rheumatoid arthritis (RA) and normal controls were detected by western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Small interfering (si)RNA was transfected using Lipofectamine ® 2000 to decrease Tim-3 expression. Following transfection, FLS were stimulated by LPS. An MTT assay, RT-PCR and western blot analysis were performed to measure cell viability, Toll-like receptor 4 (TLR4) signaling pathway-related protein expression and inflammatory cytokine release, respectively. The results of the present study indicated that Tim-3 expression was increased in FLS from patients with RA compared with FLS from healthy controls. Transfection of Tim-3 siRNA significantly decreased Tim-3 expression in FLS from patients with RA. Notably, Tim-3 silencing decreased FLS cell viability. Following stimulation with LPS, cell viability and the expression of TLR4, myeloid differentiation protein gene 88 (MyD88) and nuclear factor-κB (NF-κB) p65 were enhanced in FLS. By contrast, Tim-3 silencing attenuated LPS-induced cell proliferation and the expression of TLR4, MyD88 and NF-κB p65. In addition, LPS significantly increased levels of cytokines in the supernatant, including tumor necrosis factor-α, interferon-γ and interleukin-6 (P<0.01). By contrast, Tim-3 silencing significantly decreased LPS-induced cytokine release (P<0.01). However, Tim-3 silencing did not affect TLR4, MyD88 and NF-κB p65 expression and the release of cytokines in cells that did not undergo treatment with LPS. Therefore, the results of the present study indicate that Tim-3 silencing decreases the viability of FLS in RA and attenuates the LPS-induced inflammatory reaction.

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“…Cells were treated with a plant lectin, which is known to activate TLR4 by a mechanism different than LPS, and then with different doses of guanidinocalixarenes. A dose-dependent TLR4 inhibition was still observed, and this is suggestive of a direct effect of calixarenes on the receptor ( 40 ).…”

Section: Non-glycolipid Tlr4 Modulatorsmentioning

confidence: 94%

“…The capacity of amphiphilic calixarenes to modulate TLR4 signal was studied in cationic calix[4]arenes functionalized with guanidine groups on the upper rim (compounds 19, Figure 8 ) and anionic calix[4]arenes with carboxyl groups (compounds 20, Figure 8 ) ( 40 ).…”

Section: Non-glycolipid Tlr4 Modulatorsmentioning

confidence: 99%

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

Romerio

Peri

2020

Front. Immunol.

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Toll-Like Receptor 4 (TLR4) is one of the receptors of innate immunity. It is activated by Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) and triggers pro-inflammatory responses that belong to the repertoire of innate immune responses, consequently protecting against infectious challenges and boosting adaptive immunity. Mild TLR4 stimulation by non-toxic molecules resembling its natural agonist (lipid A) provided efficient vaccine adjuvants. The non-toxic TLR4 agonist monophosphoryl lipid A (MPLA) has been approved for clinical use. This suggests the development of other TLR4 agonists as adjuvants or drugs for cancer immunotherapy. TLR4 excessive activation by a Gram-negative bacteria lipopolysaccharide (LPS) leads to sepsis, while TLR4 stimulation by DAMPs is a common mechanism in several inflammatory and autoimmune diseases. TLR4 inhibition by small molecules and antibodies could therefore provide access to innovative therapeutics targeting sepsis as well as acute and chronic inflammations. The potential use of TLR4 antagonists as anti-inflammatory drugs with unique selectivity and a new mechanism of action compared to corticosteroids or other non-steroid anti-inflammatory drugs fueled the search for compounds of natural or synthetic origin able to block or inhibit TLR4 activation and signaling. The wide spectrum of clinical settings to which TLR4 inhibitors can be applied include autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases), vascular inflammation, neuroinflammations, and neurodegenerative diseases. The last advances (from 2017) in TLR4 activation or inhibition by small molecules (molecular weight <2 kDa) are reviewed here. Studies on pre-clinical validation of new chemical entities (drug hits) on cellular or animal models as well as new clinical studies on previously developed TLR4 modulators are reported. Innovative TLR4 modulators discovered by computer-assisted drug design and an artificial intelligence approach are described. Some “old” TLR4 agonists or antagonists such as MPLA or Eritoran are under study for repositioning in different pharmacological contexts. The mechanism of action of the molecules and the level of TLR4 involvement in their biological activity are critically discussed.

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Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)- and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling

Cited by 29 publications

References 55 publications

Bradyrhizobium Lipid A: Immunological Properties and Molecular Basis of Its Binding to the Myeloid Differentiation Protein-2/Toll-Like Receptor 4 Complex

Bradyrhizobium Lipid A: Immunological Properties and Molecular Basis of Its Binding to the Myeloid Differentiation Protein-2/Toll-Like Receptor 4 Complex

Effects of Tim-3 silencing on the viability of fibroblast-like synoviocytes and lipopolysaccharide-induced inflammatory reactions

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

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