Human Toll-Like Receptor 8-Selective Agonistic Activities in 1-Alkyl-1<i>H</i>-benzimidazol-2-amines

An approach to identify β-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2. Protein-observed NMR (two-dimensional 15N heteronuclear single-quantum coherence spectroscopy) and crystallographic studies with the soluble domain of BACE1 identified a unique and novel binding mode for compound 12, a fragment that still occupies the active site while not making any interactions with catalytic Asps. This novel approach of combining orthogonal fragment screening techniques, for both wild-type and mutant enzymes, as well as binding competition studies could be generalized to other targets to overcome undesired interaction motifs and as a hit-generation approach in highly constrained intellectual property space.

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“…53 Compound 11 was obtained from the internal compound collection and has been previously reported. 54 …”

Section: Methodsmentioning

confidence: 99%

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

et al. 2017

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“…A dataset of 137 samples including 97 hTLR8 agonists (Beesu et al, , ; Kokatla et al, ; Roethle et al, ; Salunke et al, ; Schiaffo et al, ; Shi et al, ; Yoo et al, ) and 40 antagonists (N. M. Shukla et al, ; Nikunj M. Shukla et al, ; Zhang et al, ) was derived from recent researches. The activities of hTLR8 agonists were mainly detected by human TLR8‐specific reporter gene assays, which was quantified by the induction of NF‐κB in human embryonic kidney 293 (HEK 293) cells, and the antagonists were quantified by using an engineered HEK‐Blue 293 cell line with overexpressed hTLR8.…”

Section: Methodsmentioning

confidence: 99%

“…Resiquimod (R848), the synthetic dual agonist of hTLR7/8, has been proven effective for genital herpes treatment (Kanzler, Barrat, Hessel, & Coffman, ). Subsequently, a series of imidazo‐quinazolines, thiazolo‐quinolines, furo‐quinolines, and more recent furo‐pyridines and amino‐imidazoles analogues have been discovered as potential hTLR8 agonists (Figure a) (Beesu et al, , ; Kokatla et al, ; McGowan et al, ; Salunke et al, ; Yoo et al, ). The hTLR8 antagonists currently under development are structural analogue of agonists, for example, 3H imidazoquinolines for TLR7/8 dual antagonists(Shukla, Malladi, Day, & David, ), pyrazolo[1,5‐ a ]pyrimidine derivatives and quinoline derivatives as hTLR8 antagonists (Figure b) (Zhang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Subtle differences in chemical pattern between human toll‐like receptor 8 agonists and antagonists: Emerging chemical patterns analysis

et al. 2019

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Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8. K E Y W O R D Sagonist, antagonist, emerging chemical pattern, prediction, toll-like receptor 8

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“…Recently, the X‐ray co‐crystal structure of TLR8 has been solved with a number of small‐molecule ligands . Guided by this information, structure‐based ligand design led to the identification of several additional TLR8 agonists …”

Section: Discovery From Rational Design (Inspired By Nature)mentioning

confidence: 99%

Strategies for designing synthetic immune agonists

Wu¹

2016

Immunology

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SummaryEnhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application.

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Human Toll-Like Receptor 8-Selective Agonistic Activities in 1-Alkyl-1H-benzimidazol-2-amines

Cited by 38 publications

References 76 publications

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

Subtle differences in chemical pattern between human toll‐like receptor 8 agonists and antagonists: Emerging chemical patterns analysis

Strategies for designing synthetic immune agonists

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