TY - JOUR
T1 - Receptor-Ligand Kinetics Influence the Mechanism of Action of Covalently Linked TLR Ligands
AU - Kimani, Flora W.
AU - Ajit, Jainu
AU - Galluppi, Alexander
AU - Manna, Saikat
AU - Howitz, William J.
AU - Tang, Sophia
AU - Esser-Kahn, Aaron P.
N1 - Funding Information:
The authors acknowledge the financial support provided by National Institutes of Health (7U01AI124286-03)
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/2/19
Y1 - 2021/2/19
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.0c00924
DO - 10.1021/acschembio.0c00924
M3 - Article
C2 - 33523635
AN - SCOPUS:85101945035
SN - 1554-8929
VL - 16
SP - 380
EP - 388
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 2
ER -
