Open AccessStructure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity
Author(s) -
Mallesh Beesu,
Giuseppe Caruso,
Alex C. D. Salyer,
Karishma K. Khetani,
Diptesh Sil,
M.S. Samantha Weerasinghe,
Hiromi Tanji,
Umeharu Ohto,
Toshiyuki Shimizu,
Sunil A. David
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b01087
Subject(s) - chemistry , ectodomain , agonist , potency , stereochemistry , partial agonist , structure–activity relationship , receptor , cytokine , monocyte , dendritic cell , biochemistry , immune system , in vitro , immunology , biology
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.