Toll-like receptor 7 and 8 imidazoquinoline-based agonist/antagonist pairs

Mu Yang; Peter G Larson; Lincoln Brown; John R Schultz; Tamara A Kucaba; Thomas S Griffith; David M Ferguson

doi:10.1016/j.bmcl.2022.128548

Toll-like receptor 7 and 8 imidazoquinoline-based agonist/antagonist pairs

Bioorg Med Chem Lett. 2022 Mar 1:59:128548. doi: 10.1016/j.bmcl.2022.128548. Epub 2022 Jan 18.

Authors

Mu Yang¹, Peter G Larson¹, Lincoln Brown¹, John R Schultz¹, Tamara A Kucaba², Thomas S Griffith³, David M Ferguson⁴

Affiliations

¹ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.
² Department of Urology, University of Minnesota, Minneapolis, MN 55455, United States.
³ Department of Urology, University of Minnesota, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, United States; Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455, United States.
⁴ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States; Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: ferguson@umn.edu.

PMID: 35051578
DOI: 10.1016/j.bmcl.2022.128548

Abstract

Toll-like receptors (TLRs) 7 and 8 are key targets in the development of immunomodulatory drugs for treating infectious disease, cancer, and autoimmune disorders. These receptors can adopt both agonist and antagonist binding conformations that switch the receptor signal on or off to the downstream production of cytokines. In this study, we examined the effect of simple isomeric substitutions to the C2-butyl group of two imidazoquinoline agonists and evaluated the activity of these analogs using both TLR7 and TLR8 reporter cells and cytokine induction assays. Results are presented showing the C2-isobutyl and C2-cyclopropylmethyl isomers are both mixed TLR7/8 competitive antagonists of the parent agonist [4-Amino-1-(4-(aminomethyl)benzyl)-2-butyl-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline], indicating the conformation of the dimeric receptor complex is highly sensitive to steric perturbations to the ligand binding pocket. This observation is consistent with prior work demonstrating TLR7 and TLR8 activity is directly correlated to C2-alkyl substitutions that project into a hydrophobic pocket at the dimer interface of the receptor. The close structural relationship of the agonist/antagonist pairs identified here highlights the importance of this pocket in tipping the balance between the agonist and antagonist binding states of the receptor which may have significant ramifications to the design of imidazoquinoline-based immunomodulatory agents.

Keywords: Antagonist; Drug design; Imidazoquinoline; Immunomodulator; Structure activity relationship; Synthesis; TLR7; TLR8; Toll-like receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Structure
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship
Toll-Like Receptor 7 / agonists*
Toll-Like Receptor 7 / antagonists & inhibitors*
Toll-Like Receptor 8 / agonists*
Toll-Like Receptor 8 / antagonists & inhibitors*

Substances

Imidazoles
Quinolines
TLR7 protein, human
TLR8 protein, human
Toll-Like Receptor 7
Toll-Like Receptor 8