Structure-based design of novel human Toll-like receptor 8 agonists.
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 might be promising candidate vaccine adjuvants. Recently, a C2-butyl furo[2,3-c]quinoline was reported with purely TLR8 agonistic activity. This compound was successfully co-crystallized with the human TLR8 ectodomain, and the co-crystal structure revealed ligand-induced reorganization of the binding pocket of TLR8. The loss of a key hydrogen bond between the oxygen atom of the furanyl ring of the agonist and Thr 574 in TLR8 suggested that the furan ring is dispensable. Employing a disconnection strategy, 3- and 4-substituted aminoquinolines were investigated. 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 (EC50 =0.2 μM). Preliminary evaluation of this compound in ex vivo human blood assay systems revealed that it retains prominent cytokine-inducing activity. Together, these results indicate the suitability of this compound as a novel vaccine adjuvant, warranting further investigation.
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047 (USA).
Hari Prasad
HP
Kokatla
Diptesh
D
Sil
Hiromi
H
Tanji
Umeharu
U
Ohto
Subbalakshmi S
SS
Malladi
Lauren M
LM
Fox
Toshiyoki
T
Shimizu
Sunil A
SA
David
D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D051200:Toll-Like Receptor 8 / Q000819:agonists*
D000634:Aminoquinolines; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8
aminoquinolines; innate immunity; structure-based drug design; toll-like receptor-8 (TLR8); vaccine adjuvants