Structure-based Ligand Design of Novel Human Toll-like Receptor 8 Agonists

• Published in: ChemMedChem 2014-01, Vol.9 (4), p.719-723
• Main Authors: Kokatla, Hari Prasad, Sil, Diptesh, Tanji, Hiromi, Ohto, Umeharu, Malladi, Subbalakshmi S., Fox, Lauren M., Shimizu, Toshiyoki, David, Sunil A.
• Format: Article
• Language: English
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201300573

Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We recently reported pure TLR8 agonistic activity in a C2-butyl furo[2,3- c ]quinoline. We have obtained the structure of human TLR8 ectodomain co-crystallized with the furoquinoline compound, which indicates ligand-induced reorganization of the binding pocket of TLR8. The loss of a key H-bond between the oxygen atom of the furanyl ring of the agonist and Thr574 in TLR8 suggested that the furan ring was dispensable. We employed a disconnection strategy and examined 3- and 4-substituted aminoquinolines. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist.