Structure-based design of human TLR8-specific agonists with augmented potency and adjuvanticity

Beesu M, Caruso G, Salyer AC, Khetani KK, Sil D, Weerasinghe M, Tanji H, Ohto U, Shimizu T, David SA (2015) J. Med. Chem. 58:7833-49.

Pubmed: pubmed.ncbi.nlm.nih.gov/26351878 doi: 10.1021/acs.jmedchem.5b01087

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.