Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.
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.
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Mallesh
M
Beesu
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Giuseppe
G
Caruso
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Alex C D
AC
Salyer
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Karishma K
KK
Khetani
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Diptesh
D
Sil
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Mihiri
M
Weerasinghe
Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo 113-0033, Japan.
Hiromi
H
Tanji
Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo 113-0033, Japan.
Umeharu
U
Ohto
Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo 113-0033, Japan.
Toshiyuki
T
Shimizu
Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
Sunil A
SA
David
D056704:Adaptive Immunity / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D011487:Protein Conformation; D011804:Quinolines / Q000737:chemistry; D011817:Rabbits; D013329:Structure-Activity Relationship; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000737:chemistry / Q000235:genetics
D000276:Adjuvants, Immunologic; D011804:Quinolines; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C037219:quinoline