Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors <b>7</b> and <b>8</b>

Padilla‐Salinas, Rosaura; Anderson, Rachel; Sakaniwa, Kentaro; Zhang, Shuting; Nordeen, Patrick; Lu, Chuan‐Jun; Shimizu, Toshiyuki; Yin, Hang

doi:10.1021/acs.jmedchem.9b01201

Cited by 15 publications

(16 citation statements)

References 56 publications

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“…5, Table 1; . Furthermore, several compounds consisting of two distinct chemical scaffolds equipped with TLR7/8 dual or TLR8-selective antagonistic activities have recently been discovered (Padilla-Salinas et al, 2019).…”

Section: Inactivated Forms Of Tlr8 Stabilized By Antagonistsmentioning

confidence: 99%

Targeting the innate immune receptor TLR8 using small-molecule agents

Sakaniwa

Shimizu

2020

Acta Crystallogr D Struct Biol

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Toll-like receptors (TLRs) are pattern-recognition receptors that initiate innate immune responses. Among the TLRs, TLR8 (and TLR7) recognizes single-stranded RNA to mediate downstream signals. In recent years, intensive X-ray crystal structural analyses have provided atomic insights into structures of TLR8 complexed with various agonists or antagonists. Here, structural knowledge of the activation and inactivation mechanisms of the ligands is reviewed. In addition, the potential clinical applications of TLR ligands are examined.

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Section: Inactivated Forms Of Tlr8 Stabilized By Antagonistsmentioning

confidence: 99%

Targeting the innate immune receptor TLR8 using small-molecule agents

Sakaniwa

Shimizu

2020

Acta Crystallogr D Struct Biol

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“…Yin’s lab identified a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif and a modest TLR7 and TLR8 dual inhibitor bearing a benzanilide scaffold. Both were selected for extensive SAR studies, and critical distinct scaffolds were established and optimized for each kind of inhibitor to enhance their specificity …”

Section: Tlr8mentioning

confidence: 99%

“…Both were selected for extensive SAR studies, and critical distinct scaffolds were established and optimized for each kind of inhibitor to enhance their specificity. 59…”

Section: ■ Tlr7mentioning

confidence: 99%

Small-Molecule Modulators of Toll-like Receptors

et al. 2020

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Metrics & MoreArticle Recommendations CONSPECTUS: Toll-like receptors (TLRs) are the "gatekeepers" of the immune system in humans and other animals to protect the host from invading bacteria, viruses, and other microorganisms. Since TLR4 was discovered as the receptor for endotoxin in the late 1990s, significant progress has been made in exploiting an understanding of the function of TLRs.The TLR-signaling pathway is crucial for the induction and progression of various diseases. Dysregulation of TLR signaling contributes to numerous pathological conditions, including chronic inflammation, sepsis, cancers, asthma, neuropathic pain, drug addiction, and autoimmune diseases. Therefore, manipulation of TLR signaling is promising to halt their activity in inflammatory diseases, to enhance their signaling to fight cancers, to modulate their role in autoimmune diseases, and to suppress them to treat drug addiction. TLR agonists have demonstrated great potential as antimicrobial agents and vaccine adjuvants, whereas TLR antagonists are being developed as reagents and drugs to dampen immune responses. Because of their pivotal potential therapeutic applications, fruitful small-molecule compounds and peptide fragments have been discovered, and many of them have advanced to various stages of clinical trials (though only two have been approved by the Food and Drug Administration (FDA): MPLA as a TLR4 agonist and imiquimod as a TLR7 agonist).In this Account, we focus on the progress in developing TLR signaling pathway modulators (mainly focused on the Yin and Wang laboratories) over the past decade and highlight the accomplishments and currently existing challenges in the development of TLR modulators. First, we briefly describe the members of the human TLR family along with their natural modulators. Second, we illustrate our endeavors to discover TLR-targeted agents using comprehensive approaches. Specifically, a discussion of identification and characterization of new chemical entities, determination of modes of action, and further applications is presented. For instance, the TLR3 antagonist was first discovered through in silico screening, and the inhibitory activity was confirmed in murine cells.Considering the glycosylation on TLR3, a new direction for TLR3 modulator design was pointed out to target asparagine glycosylation. We have particularly focused on the discovery of TLR4 antagonists and have assessed their great potential in the clinical treatment of drug addiction and alcohol use disorders. In addition, we discuss multiple other popular and robust techniques for modulator discovery. Not only small organic modulators but also stapled peptides and peptidomimetics will attract more and more attention in the future. Finally, current challenges, opportunities, and future perspectives for TLR-targeted agents are also discussed.

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“…Benzanilide 145 (Figure ) was obtained from the HTS of a library of 14 400 compounds . The SAR study involving replacing one of the −CF 3 groups in 145 with a −H in ring A had revealed that one −CF 3 group was sufficient to hold the TLR7 and TLR8.…”

Section: Structural Evolution: Structure–activity Relationship Develo...mentioning

confidence: 99%

“…Benzanilide 145 (Figure 44) was obtained from the HTS of a library of 14 400 compounds. 131 The SAR study involving replacing one of the −CF 3 groups in 145 with a −H in ring A had revealed that one −CF 3 group was sufficient to hold the TLR7 and TLR8. Interestingly, switching the −CF 3 group to −F in 146 weakened the TLR7 activity with the retention of TLR8 activity.…”

Section: Structural Evolution and Structure−activity Relationship Of ...mentioning

confidence: 99%

Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors

et al. 2021

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Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self-and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after. Recent research has revealed that agonists and antagonists share an overlapping binding region. This Perspective highlights rational medicinal chemistry approaches to elucidate the structural attributes of small molecules capable of agonism or antagonism or of elegantly switching between the two. The structural evolution of different chemotypes can provide the framework for the future development of endosomal TLR agonists and antagonists.

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Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8

Cited by 15 publications

References 56 publications

Targeting the innate immune receptor TLR8 using small-molecule agents

Targeting the innate immune receptor TLR8 using small-molecule agents

Small-Molecule Modulators of Toll-like Receptors

Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors

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