Recent progress in the development of Toll-like receptor (TLR) antagonists

Patra, Mahesh Chandra; Choi, Sangdun

doi:10.1080/13543776.2016.1185415

Cited by 72 publications

(73 citation statements)

References 94 publications

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“…We note that the ability of TLR2 activation to direct metabolic changes is aligned with high TLR2‐expressing cancer cell lines, namely MKN1 and NUGC4, which is a clinically‐relevant observation since TLR2 expression is augmented in >50% of human GC cases . In this respect, it is noteworthy that both TLR agonists and antagonists have been actively exploited for their safety and therapeutic efficacy as adjuvants or monotherapy in trials for metastatic diseases . Our findings reveal that TLR2 expression levels and activation can influence the metabolic state, and thus proliferative potential of cancer cells.…”

Section: Discussionmentioning

confidence: 54%

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Liu

Ying

et al. 2019

Intl Journal of Cancer

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Toll‐like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial‐ and host‐derived components, and their dysregulation is a common feature of various inflammation‐associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand‐induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray‐based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene‐sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese‐dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK‐STAT3, JNK MAPK and NF‐κB. Furthermore, siRNA‐mediated suppression of SOD2 ameliorated the TLR2‐induced metabolic shift in human GC cancer cells. Importantly, patient‐derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2‐SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2‐SOD2 axis as a potential biomarker for therapy and prognosis in cancer.

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Section: Discussionmentioning

confidence: 54%

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Liu

Ying

et al. 2019

Intl Journal of Cancer

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“…Because a link between TLR4 activation and NAFLD progression has begun to be understood, the use of TLR4 inhibitor as an anti‐NAFLD agent should attract interest. Considering the therapeutic importance of down‐modulation of TLR4 signaling in patients with such life‐threatening diseases as sepsis and inflammatory bowel disease, pharmaceutical companies and laboratories have developed numerous TLR4 antagonists; some of them are either in or have completed clinical trials . Although two well‐known TLR4 antagonists, TAK‐242 and Eritoran, could not reach the market due, not to safety considerations, but to an inadequate clinical outcome (about 28‐day all‐cause mortality) in a phase 3 study of patients with severe sepsis, other candidates with increased potency have entered clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Identification of hepatic NPC1L1 as an NAFLD risk factor evidenced by ezetimibe‐mediated steatosis prevention and recovery

et al. 2019

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Non‐alcoholic fatty liver disease (NAFLD) is a serious global public health concern. Nevertheless, there are no specific medications for treating the associated abnormal accumulation of hepatic lipids such as cholesterol and triglycerides. While seminal findings suggest a link between hepatic cholesterol accumulation and NAFLD progression, the molecular bases of these associations are not well understood. Here, we experimentally demonstrate that hepatic Niemann‐Pick C1‐Like 1 (NPC1L1), a cholesterol re‐absorber from bile to the liver, can cause steatosis, an early stage of NAFLD using genetically engineered L1‐Tg mice characterized by hepatic expression of NPC1L1 under the control of ApoE promoter. Contrary to wild‐type mice that have little expression of hepatic Npc1l1, the livers of L1‐Tg mice fed a high‐fat diet became steatotic within only a few weeks. Moreover, hepatic NPC1L1‐mediated steatosis was not only prevented, but completely rescued, by orally administered ezetimibe, a well‐used lipid‐lowering drug on the global market, even under high‐fat diet feedings. These results indicate that hepatic NPC1L1 is an NAFLD‐exacerbating factor amendable to therapeutic intervention and would extend our understanding of the vital role of cholesterol uptake from bile in the development of NAFLD. Furthermore, administration of a TLR4 inhibitor also prevented the hepatic NPC1L1‐mediated steatosis formation, suggesting a latent link between physiological roles of hepatic NPC1L1 and regulation of innate immune system. Our results revealed that hepatic NPC1L1 is a novel NAFLD risk factor contributing to steatosis formation that is rescued by ezetimibe; additionally, our findings uncover feasible opportunities for repositioning drugs to treat NAFLD in the near future.

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“…TLR antagonists are regulators that inhibit or reduce activation of TLRmediated cytokine cascades and check over-reactive uncontrolled adaptive immune responses. TLR antagonists are generally modified agonists that bind TLRs but fail to induce the signal transduction [69,283]. Recently highlighting the existence of antagonist pockets on TLRs 7/8 will also allow specific structure-based design using molecular modeling tools to produce new potent structures [9,284].…”

Section: Antagonist Ligandsmentioning

confidence: 99%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

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Recent progress in the development of Toll-like receptor (TLR) antagonists

Cited by 72 publications

References 94 publications

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Identification of hepatic NPC1L1 as an NAFLD risk factor evidenced by ezetimibe‐mediated steatosis prevention and recovery

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

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