Open AccessReceptor–Ligand Kinetics Influence the Mechanism of Action of Covalently Linked TLR Ligands
Author(s) -
Flora W. Kimani,
Jainu Ajit,
Alexander Galluppi,
Saikat Manna,
William J. Howitz,
Sophia Tang,
Aaron P. EsserKahn
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.0c00924
Subject(s) - agonist , receptor , chemistry , ligand (biochemistry) , kinetics , tumor necrosis factor alpha , microbiology and biotechnology , cytokine , toll like receptor , immune system , biophysics , receptor–ligand kinetics , t cell receptor , mechanism of action , in vitro , enhancer , biochemistry , biology , t cell , immunology , innate immune system , gene expression , gene , physics , quantum mechanics
We report a mechanistic study comparing the immune activation of conjugated Toll-like receptor (TLR) agonists and their unlinked mixtures. Herein, we synthesized a set of six linked dual agonists with different ligands, molecular structures, receptor locations, and biophysical characteristics. With these dimers, we ran a series of in vitro cell-based assays, comparing initial and overall NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, cytokine expression profiles, as well as time-resolved TNF-α (Tumor Necrosis Factor alpha) expression. We show that initial activation kinetics, ligand specificity, and the dose of the agonist influence the activity of these linked TLR systems. These results can help improve vaccine design by showing how linked TLR agonists can improve their potency with the appropriate selection of key criteria.