Structure-based design of novel human toll-like receptor 8 agonists

Hari Prasad Kokatla, Diptesh Sil, Hiromi Tanji, Umeharu Ohto, Subbalakshmi S. Malladi, Lauren M. Fox, Toshiyoki Shimizu, Sunil A. David

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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. Designer adjuvants: Focused ligand design studies based on the co-crystal structure of human toll-like receptor-8 (TLR8) ectodomain led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist, a promising new class of vaccine adjuvants.

Original languageEnglish (US)
Pages (from-to)719-723
Number of pages5
JournalChemMedChem
Volume9
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • aminoquinolines
  • innate immunity
  • structure-based drug design
  • toll-like receptor-8 (TLR8)
  • vaccine adjuvants

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