Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity

Mallesh Beesu, Giuseppe Caruso, Alex C D Salyer, Karishma K. Khetani, Diptesh Sil, Mihiri Weerasinghe, Hiromi Tanji, Umeharu Ohto, Toshiyuki Shimizu, Sunil A. David

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)7833-7849
Number of pages17
JournalJournal of medicinal chemistry
Issue number19
StatePublished - Oct 8 2015

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© 2015 American Chemical Society.


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