Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity

Abstract

Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by “designing in” functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.

Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands

“…In this study, to address these questions, we report a comprehensive structural analysis of TLR7 with a total of 21 cocrystal structures of TLR7-ligand complexes. We cocrystallized TLR7 with (1) 13 types of six-base U-containing ssRNAs, together with IMDQ (a TLR7 and TLR8 agonist) (Beesu et al, 2015);…”

Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators

“…David and colleagues (University of Kansas and University of Tokyo) recently reported a structure‐based design approach toward human TLR8‐specific agonists with enhanced potency . Crystal structures of the ectodomain of hTLR8 co‐crystallized with two regioisomers of a dual TLR7/8‐agonistic N1‐substituted imidazoquinoline 64 showed small differences in their interactions in the binding site of hTLR8 (Figure ).…”

Discovery and Biological Evaluation of New Selective Acetylcholinesterase Inhibitors with Anti-Aβ Aggregation Activity through Molecular Docking-Based Virtual Screening

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