Development of β-Amino Alcohol Derivatives That Inhibit Toll-like Receptor 4 Mediated Inflammatory Response as Potential Antiseptics

Chavez, Sherry A.; Martinko, Alexander J.; Lau, Corinna; Pham, Michael N.; Cheng, Kui; Bevan, Douglas; Mollnes, Tom Eirik; Yin, Hang

doi:10.1021/jm2003365

Cited by 30 publications

(24 citation statements)

References 45 publications

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“…To address the viability of targeting MD2/TLR4 complex formation for inhibiting fibrosis, we searched for novel compounds to selectively block the pathway, taking advantage of the MD2 coactivator requirement unique to TLR4, but not other TLRs, for MD2 (7). High-throughput in silico screening of a drug-like library identified a pharmacologically auspicious β-amino alcohol derivative (T5342126) as a potentially novel TLR4 inhibitor (22)(23)(24). Based on molecular-docking stimulation, this small molecule is predicted to compete with MD2 for binding to TLR4, thus preventing formation of the signaling-competent TLR4 complex (9,25).…”

Section: Resultsmentioning

confidence: 99%

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung

Bhattacharyya

Wang²,

Qin

et al. 2018

JCI Insight

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Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation.

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Section: Resultsmentioning

confidence: 99%

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung

Bhattacharyya

Wang²,

Qin

et al. 2018

JCI Insight

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“…Representative recordings (Figure 3A) and grouped data (Figure 3B) demonstrate that the excitability of these neurons was significantly increased by LPS when compared with control levels. We utilized a previously reported small molecule inhibitor, Compound 15 [13,20], as a chemical probe to further investigate the molecular mechanism of M3G-induced neuron response. The ability of Compound 15 to disrupt the TLR4/MD-2 complex formation and selectively block TLR4 signal transduction without affecting other homologous TLR family proteins has been previously demonstrated [13].…”

Section: Resultsmentioning

confidence: 99%

“…The ability of Compound 15 to disrupt the TLR4/MD-2 complex formation and selectively block TLR4 signal transduction without affecting other homologous TLR family proteins has been previously demonstrated [13]. Further, Compound 15 was screened against a panel of 12 representative kinases, showing negligible non-specific inhibitory effects [20]. Importantly, Compound 15 demonstrated high specificity and low toxicity both in vitro and in vivo [21], providing an excellent probing tool to study the TLR4-specific signal transduction.…”

Section: Resultsmentioning

confidence: 99%

Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling

Due

Piekarz

Wilson

et al. 2012

J Neuroinflammation

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121

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BackgroundMultiple adverse events are associated with the use of morphine for the treatment of chronic non-cancer pain, including opioid-induced hyperalgesia (OIH). Mechanisms of OIH are independent of opioid tolerance and may involve the morphine metabolite morphine-3-glucuronide (M3G). M3G exhibits limited affinity for opioid receptors and no analgesic effect. Previous reports suggest that M3G can act via the Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) heterodimer in the central nervous system to elicit pain.MethodsImmunoblot and immunocytochemistry methods were used to characterize the protein expression of TLR4 present in lumbar dorsal root ganglion (DRG). Using in vitro intracellular calcium and current clamp techniques, we determined whether TLR4 activation as elicited by the prototypical agonists of TLR4, lipopolysaccharide (LPS) and M3G, contributed to changes in intracellular calcium and increased excitation. Rodents were also injected with M3G to determine the degree to which M3G-induced tactile hyperalgesia could be diminished using either a small molecule inhibitor of the MD-2/TLR4 complex in rats or TLR4 knockout mice. Whole cell voltage-clamp recordings were made from small- and medium-diameter DRG neurons (25 μm < DRG diameter <45 μm) for both control and M3G-treated neurons to determine the potential influence on voltage-gated sodium channels (NaVs).ResultsWe observed that TLR4 immunoreactivity was present in peptidergic and non-peptidergic sensory neurons in the DRG. Non-neuronal cells in the DRG lacked evidence of TLR4 expression. Approximately 15% of assayed small- and medium-diameter sensory neurons exhibited a change in intracellular calcium following LPS administration. Both nociceptive and non-nociceptive neurons were observed to respond, and approximately 40% of these cells were capsaicin-insensitive. Increased excitability observed in sensory neurons following LPS or M3G could be eliminated using Compound 15, a small molecule inhibitor of the TLR4/MD-2 complex. Likewise, systemic injection of M3G induced rapid tactile, but not thermal, nociceptive behavioral changes in the rat, which were prevented by pre-treating animals with Compound 15. Unlike TLR4 wild-type mice, TLR4 knockout mice did not exhibit M3G-induced hyperalgesia. As abnormal pain sensitivity is often associated with NaVs, we predicted that M3G acting via the MD-2/TLR4 complex may affect the density and gating of NaVs in sensory neurons. We show that M3G increases tetrodotoxin-sensitive and tetrodotoxin-resistant (NaV1.9) current densities.ConclusionsThese outcomes provide evidence that M3G may play a role in OIH via the TLR4/MD-2 heterodimer complex and biophysical properties of tetrodotoxin-sensitive and tetrodotoxin-resistant NaV currents.

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“…35 These compounds showed no cytotoxic activity at concentrations up to 300 µM, and the easily modified and scalable synthesis could provide more potent antagonists, studying a different arrangement of the aromatic substituents. 36 …”

Section: Synthetic Tlr4 Modulatorsmentioning

confidence: 99%

Toll-like Receptor 4 (TLR4) Modulation by Synthetic and Natural Compounds: An Update

2013

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Toll-like receptor 4 (TLR4), together with MD-2, binds bacterial endotoxins (E) with high affinity, triggering formation of the activated homodimer (E-MD-2-TLR4)2. Activated TLR4 induces intracellular signaling leading to activation of transcription factors that result in cytokine and chemokine production and initiation of inflammatory and immune responses. TLR4 also responds to endogenous ligands called danger associated molecular patterns (DAMPs). Increased sensitivity to infection and a variety of immune pathologies have been associated with either too little or too much TLR4 activation. We review here the molecular mechanisms of TLR4 activation (agonism) or inhibition (antagonism) by small organic molecules of both natural and synthetic origin. The role of co-receptors MD-2 and CD14 in the TLR4 modulation process is also discussed. Recent achievements in the field of chemical TLR4 modulation are reviewed, with special focus on non-classical TLR4 ligands with a chemical structure different from lipid A.

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Development of β-Amino Alcohol Derivatives That Inhibit Toll-like Receptor 4 Mediated Inflammatory Response as Potential Antiseptics

Cited by 30 publications

References 45 publications

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung

Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling

Toll-like Receptor 4 (TLR4) Modulation by Synthetic and Natural Compounds: An Update

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