Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure–Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds

Yoo, Euna; Salunke, Deepak B.; Sil, Diptesh; Guo, Xiaoqiang; Salyer, Alex C. D.; Hermanson, Alec R.; Kumar, Manoj; Malladi, Subbalakshmi S.; Balakrishna, Rajalakshmi; Thompson, Ward H.; Tanji, Hiromi; Ohto, Umeharu; Shimizu, Toshiyuki; David, Sunil A.

doi:10.1021/jm500744f

Cited by 62 publications

(77 citation statements)

References 45 publications

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“…For example, the specific TLR7 agonist compound 30 (EC50 ¼ 0.26 mM) displayed high IFNa induction in human PBMCs. Since some of these compounds are potent inducers of type I IFN, with an attenuated proinflammatory profiles, they could be potent adjuvants without local or systemic inflammation reactions [134].…”

Section: Pyrimidine and Purine Base Derivativesmentioning

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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Section: Pyrimidine and Purine Base Derivativesmentioning

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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“…TLR7 and TLR8 are also activated by certain small molecules with immunomodulatory properties. Recent crystal structures have revealed how TLR8 [14] and TLR9 [19] form homodimers without the presence of ligands, consistent with the large buried area formed between chains. Whilst no crystal structure is available for TLR7, the 43% sequence identity to TLR8 suggests that the structure of the dimeric complex should be conserved [16,18].…”

Section: Tlr3 Homodimermentioning

confidence: 72%

“…TLR5 is stimulated by flagellin, a protein involved in motility in many bacteria. In contrast, TLR3, 7, 8 and 9 are activated by viral pathogenic molecules [13][14][15][16], namely: TLR3, double stranded RNA [17] associated with many viruses; TLR7 and 8, single stranded RNA present in viruses such as Ebola [14][15][16]18]; TLR9, CpG-rich DNA, a form of DNA prevalent in viral and bacterial genomes [19].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Strikingly, the rearrangement of the TLR8 complex also causes the ectodomains to tilt (Figs 2A, B), bringing their carboxyterminal ends into closer proximity, from ~5 nm to ~3 nm separation. It is speculated that this would enable the intracellular TIR domains to dimerize in the full-length protein, thus facilitating formation of a platform for recruitment of adaptor proteins to initiate downstream signaling [14][15][16]18].…”

Section: Tlr3 Homodimermentioning

confidence: 99%

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The role of protein–protein interactions in Toll-like receptor function

Berglund

Kargas

Ortiz-Suarez

et al. 2015

Progress in Biophysics and Molecular Biology

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As part of the innate immune system, the Toll-like receptors (TLRs) represent key players in the first line of defense against invading foreign pathogens, and are also major targets for therapeutic immunomodulation. TLRs are type I transmembrane proteins composed of an ectodomain responsible for ligand binding, a single-pass transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) signaling domain. The ectodomains of TLRs are specialized for recognizing a wide variety of pathogen-associated molecular patterns, ranging from lipids and lipopeptides to proteins and nucleic acid fragments. The members of the TLR family are highly conserved and their ectodomains are composed of characteristic, solenoidal leucine-rich repeats (LRRs). Upon ligand binding, these rigid LRR scaffolds dimerize (or re-organize in the case of pre-formed dimers) to bring together their carboxy-terminal transmembrane and TIR domains. The latter are proposed to act as a platform for recruitment of adaptor proteins and formation of higher-order complexes, resulting in propagation of downstream signaling cascades. In this review, we discuss the protein-protein interactions critical for formation and stability of productive, ligand-bound TLR complexes. In particular, we focus on the large body of high-resolution crystallographic data now available for the ectodomains of homo-and heterodimeric TLR complexes, as well as inhibitory TLR-like receptors, and also consider computational approaches that can facilitate our understanding of the ligand-induced conformational changes associated with TLR function. We also briefly consider what is known about the protein-protein interactions involved in both TLR transmembrane domain assembly and TIRmediated signaling complex formation in light of recent structural and biochemical data.

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“…As yet, current experimental studies on TLR8 agonists are focused on limited chemotypes, and the information of TLR8 agonist binding has not been fully exploited. Recently, six X-ray crystal structures of TLR8 in complex with cognate agonists are available in Protein Data Bank (PDB IDs: 3W3J, 3W3K, 3W3N, 3WN4, 4Q8Z, and 4QC0) (12)(13)(14). Therefore, it is of great interest to identify novel TLR8 smallmolecule agonists through in silico strategies.…”

mentioning

confidence: 99%

Enrichment Assessment of Multiple Virtual Screening Strategies for Toll‐Like Receptor 8 Agonists Based on a Maximal Unbiased Benchmarking Data Set

et al. 2015

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Toll-like receptor 8 agonists, which activate adaptive immune responses by inducing robust production of T-helper 1-polarizing cytokines, are promising candidates for vaccine adjuvants. As the binding site of toll-like receptor 8 is large and highly flexible, virtual screening by individual method has inevitable limitations; thus, a comprehensive comparison of different methods may provide insights into seeking effective strategy for the discovery of novel toll-like receptor 8 agonists. In this study, the performance of knowledge-based pharmacophore, shape-based 3D screening, and combined strategies was assessed against a maximum unbiased benchmarking data set containing 13 actives and 1302 decoys specialized for toll-like receptor 8 agonists. Prior structure-activity relationship knowledge was involved in knowledge-based pharmacophore generation, and a set of antagonists was innovatively used to verify the selectivity of the selected knowledge-based pharmacophore. The benchmarking data set was generated from our recently developed 'mubd-decoymaker' protocol. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore (Phar1) screening, shape-based 3D similarity search (Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists.

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Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure–Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds

Cited by 62 publications

References 45 publications

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

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

The role of protein–protein interactions in Toll-like receptor function

Enrichment Assessment of Multiple Virtual Screening Strategies for Toll‐Like Receptor 8 Agonists Based on a Maximal Unbiased Benchmarking Data Set

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