TLR4 biased small molecule modulators

Lin, Cong; Wang, Hongshuang; Miyuan, Zhang; Mustafa, Sanam; Wang, Yibo; Li, Hongyuan; Yin, Hang; Hutchinson, Mark R.; Wang, Xiaohui

doi:10.1016/j.pharmthera.2021.107918

Cited by 40 publications

(37 citation statements)

References 79 publications

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“…Extensive studies have demonstrated that the contribution of activated glia and their pro-inflammatory products to allodynia and that TLR4/MD-2 could be a novel drug target for treating neuropathic pain ( 7 , 8 , 56 ). Consequently, several TLR4 antagonists have been developed ( 6 , 57 , 58 ). However, few of these could cross BBB.…”

Section: Manuscript Formattingmentioning

confidence: 99%

“…Toll-like receptor 4 (TLR4) is a pattern recognition receptor (PRR), which is responsible for the recognition of pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and xenobiotic-associated molecular patterns (XMAPs) ( 6 ). Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is a natural ligand of TLR4 ( 6 ). In the central nervous system(CNS), TLR4 is primarily expressed on microglia ( 7 ), functioning mainly in the regulation of pro-inflammatory factors production.…”

Section: Introductionmentioning

confidence: 99%

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ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

Lin

Jiang

et al. 2022

Front. Immunol.

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Neuropathic pain is a common and challenging neurological disease, which renders an unmet need for safe and effective new therapies. Toll-like receptor 4 (TLR4) expressed on immune cells in the central nervous system arises as a novel target for treating neuropathic pain. In this study, ACT001, an orphan drug currently in clinical trials for the treatment of glioblastoma, was identified as a TLR4 antagonist. In vitro quenching titrations of intrinsic protein fluorescence and saturation transfer difference (STD)-NMR showed the direct binding of ACT001 to TLR4 co-receptor MD2. Cellular thermal shift assay (CETSA) showed that ACT001 binding affected the MD2 stability, which implies that MD2 is the endogenous target of ACT001. In silico simulations showed that ACT001 binding decreased the percentage of hydrophobic area in the buried solvent-accessible surface areas (SASA) of MD2 and rendered most regions of MD2 to be more flexible, which is consistent with experimental data that ACT001 binding decreased MD2 stability. In keeping with targeting MD2, ACT001 was found to restrain the formation of TLR4/MD2/MyD88 complex and the activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream pro-inflammatory factors NO, IL-6, TNF-α, and IL-1β. Furthermore, systemic administration of ACT001 attenuated allodynia induced by peripheral nerve injury and activation of microglia and astrocyte in vivo. Given the well-established role of neuroinflammation in neuropathic pain, these data imply that ACT001 could be a potential drug candidate for the treatment of chronic neuropathic pain.

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Section: Manuscript Formattingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

Lin

Jiang

et al. 2022

Front. Immunol.

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“…So, the TLR4 immunoreactivity detected in our study could be indicative of signaling from both the membrane through Myd88 and internally from TRIF, as well as the MyD88 immunoreactivity could be somehow non-specific for TLR4 and may include other TLRs (Biswas, 2018). Nevertheless, even if different pathways are activated, all of them converge and activate the NF-κB factor, in which we are particularly interested because it is the foremost important transcriptional manager of inflammation-associated genes (Marongiu et al, 2019;Ciesielska et al, 2021;Lin et al, 2021;Duan et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: findings in preclinical models and in a postmortem human case”

Moya

Escudero

Gómez-Blázquez

et al. 2022

Preprint

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Wernicke encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder (AUD) its main risk factor. WE patients present limiting motor, cognitive and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed as one of the phenomena contributing to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR) 4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet and receiving pyrithiamine). However, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. Additionally, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD; TD diet + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or a combined treatment (CA+TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its co-receptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFkappaB; p65 and IkappaB, in the post-mortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NFkappaB and IkappaB in the CA+TDD animal model. In the patient diagnosed with alcohol-induced WE we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Thus, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in WE related to alcohol consumption.

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“…TLR4 is a key member of the TLRs family, which forms a complex on the cell surface with myeloid differentiation protein 2 (MD2) ( 4 ). Lipopolysaccharide (LPS), a significant component of the outer wall of Gram-negative bacteria, is the natural ligand of TLR4 as PAMPs ( 5 ). Besides for PAMPs, TLR4 also recognizes damages-associated molecular patterns (DAMPs) and xenobiotic-associated molecular patterns (XAMPs) ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…Lipopolysaccharide (LPS), a significant component of the outer wall of Gram-negative bacteria, is the natural ligand of TLR4 as PAMPs ( 5 ). Besides for PAMPs, TLR4 also recognizes damages-associated molecular patterns (DAMPs) and xenobiotic-associated molecular patterns (XAMPs) ( 5 ). The high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70) and the myeloid-related protein 8 (MRP8) are the endogenous ligands of TLR4 as DAMPs ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia

Wang

Lin

et al. 2022

Front. Immunol.

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Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation. In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with in silico simulations that CBDV binding increased the flexibility of the internal loop of MD2. Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent. This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.

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TLR4 biased small molecule modulators

Cited by 40 publications

References 79 publications

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

“Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: findings in preclinical models and in a postmortem human case”

Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia

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