Targeting the innate immune receptor TLR8 using small-molecule agents

Sakaniwa, Kentaro; Shimizu, Toshiyuki

doi:10.1107/s2059798320006518

Cited by 12 publications

(10 citation statements)

References 48 publications

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“…All the docked complexes with various TLRs were found energetically favourable, indicated by negative values of ΔG. Current study utilizes the TLRs located on cell surfaces (TLR2, TLR4 and TLR5) as well as TLRs located in endosomes (TLR3, TLR7 and TLR8) (Sakaniwa and Shimizu 2020 ). TLRs are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) of various microbes and play a vital role in innate immune responses.…”

Section: Discussionmentioning

confidence: 99%

Designing a next generation multi-epitope based peptide vaccine candidate against SARS-CoV-2 using computational approaches

Saha¹,

Ghosh

Burra³

2021

3 Biotech

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COVID-19 caused by SARS-CoV-2 was declared a global pandemic by WHO (World Health Organization) in March, 2020. Within 6 months, nearly 750,000 deaths are claimed by COVID-19 across the globe. This called for immediate social, scientific, technological, public and community interventions. Considering the severity of infection and the associated mortalities, global efforts are underway to develop preventive measures against SARS-CoV-2. Among the SARS-CoV-2 target proteins, Spike (S) glycoprotein (a.k.a S Protein) is the most studied target known to trigger strong host immune response. A detailed analysis of S protein-based epitopes enabled us to design a novel B-cell-derived T-cell Multi-epitope-based peptide (MEBP) vaccine candidate. This involved a systematic and comprehensive computational protocol consisting of prediction of dual-purpose epitopes and designing an MEBP vaccine construct. This was followed by 3D structure validation, MEBP complex interaction studies, in silico cloning and vaccine dose-based immune response simulation to evaluate the immunogenic potency of the vaccine construct. The dual-purpose epitope prediction protocol was designed such that the same epitope elicits both humoral and cellular immune response unlike the earlier designs. Further, the epitopes predicted were screened against stringent criteria to ensure selection of a potent candidate with maximum antigen coverage and best immune response. The vaccine dose-based immune response simulation studies revealed a rapid antigen clearance through antibody generation and elevated levels of cell-mediated immunity during repeated exposure of the vaccine. The favourable results of the analysis strongly indicate that the vaccine construct is indeed a potent vaccine candidate and ready to proceed to the next steps of experimental validation and efficacy studies.

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Section: Discussionmentioning

confidence: 99%

Designing a next generation multi-epitope based peptide vaccine candidate against SARS-CoV-2 using computational approaches

Saha¹,

Ghosh

Burra³

2021

3 Biotech

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“…TLR8 belongs to the TLR7/8/9 family of Toll-like receptors, mainly distributed in myeloid monocytes, macrophages, etc. [8]. Activation of TLR8 recruits the homologous domain containing adaptor MyD88, which attracts and activates the protein kinases IRAK4 and IRAK2.…”

Section: Introductionmentioning

confidence: 99%

African Swine Fever Virus A528R Inhibits TLR8 Mediated NF-κB Activity by Targeting p65 Activation and Nuclear Translocation

Liu

Jiang

et al. 2021

Viruses

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African swine fever (ASF) is mainly an acute hemorrhagic disease which is highly contagious and lethal to domestic pigs and wild boars. The global pig industry has suffered significant economic losses due to the lack of an effective vaccine and treatment. The African swine fever virus (ASFV) has a large genome of 170–190 kb, encoding more than 150 proteins. During infection, ASFV evades host innate immunity via multiple viral proteins. A528R is a very important member of the polygene family of ASFV, which was shown to inhibit IFN-β production by targeting NF-κB, but its mechanism is not clear. This study has shown that A528R can suppress the TLR8-NF-κB signaling pathway, including the inhibition of downstream promoter activity, NF-κB p65 phosphorylation and nuclear translocation, and the antiviral and antibacterial activity. Further, we found the cellular co-localization and interaction between A528R and p65, and ANK repeat domains of A528R and RHD of p65 are involved in their interaction and the inhibition of p65 activity. Therefore, we conclude that A528R inhibits TLR8-NF-κB signaling by targeting p65 activation and nuclear translocation.

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“…TLR8, TLR7, and TLR9 have conserved structure, cell localization, and activation mechanism and constitute a subfamily amongst TLRs [7]. Similar to other TLRs, TLR8 is a type I transmembrane glycoprotein with a ligand-binding large N-terminal ectodomain (ECD), a single transmembrane helical region, and a C-terminal cytoplasmic toll-interleukin-1 receptor (TIR) domain, among which, TLR8-ECD consists of 26 conserved leucine-rich repeats (LRRs) with a 30-40 amino acid long Z-loop domain between LRR14 and LRR15 [8]. TLR8 and TLR7 can recognize single-stranded RNA (ssRNA) and small molecular imidazoquinoline derivatives and other ligands [9].…”

Section: Introductionmentioning

confidence: 99%

The Signal Peptide and Chaperone UNC93B1 Both Influence TLR8 Ectodomain Intracellular Endosomal Localization

Liu

Jiang

et al. 2021

Vaccines

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Toll-like receptor 8 (TLR8) is a single-stranded RNA sensing receptor and is localized in the cellular compartments, where it encounters foreign or self-nucleic acids and activates innate and adaptive immune responses. However, the mechanism controlling intracellular localization TLR8 is not completely resolved. We previously revealed the intracellular localization of TLR8 ectodomain (ECD), and in this study, we investigated the mechanism of the intracellular localization. Here we found that TLR8 ECDs from different species as well as ECDs from different TLRs are all intracellularly localized, similarly to the full-length porcine TLR8. Furthermore, porcine, bovine, and human TLR8 ECDs are all localized in cell endosomes, reflecting the cellular localization of TLR8. Intriguingly, none of post-translational modifications at single sites, including glycosylation, phosphorylation, ubiquitination, acetylation, and palmitoylation alter porcine TLR8-ECD endosomal localization. Nevertheless, the signal peptide of porcine TLR8-ECD determines its endosomal localization. On the other hand, signaling regulator UNC93B1 also decides the endosomal localization of porcine, bovine, and human TLR8 ECDs. The results from this study shed light on the mechanisms of not only TLR8 intracellular localization but also the TLR immune signaling.

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Targeting the innate immune receptor TLR8 using small-molecule agents

Cited by 12 publications

References 48 publications

Designing a next generation multi-epitope based peptide vaccine candidate against SARS-CoV-2 using computational approaches

Designing a next generation multi-epitope based peptide vaccine candidate against SARS-CoV-2 using computational approaches

African Swine Fever Virus A528R Inhibits TLR8 Mediated NF-κB Activity by Targeting p65 Activation and Nuclear Translocation

The Signal Peptide and Chaperone UNC93B1 Both Influence TLR8 Ectodomain Intracellular Endosomal Localization

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