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.