Toll-like receptors (TLRs) are a family of conserved pattern recognition receptors that recognize pathogen associated molecular patterns and serve as primary sensors of the innate immune system. Signaling by TLRs can serve to couple innate immune responses with downstream adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. Agonists of TLR8, in particular, induce the production of Th1-biasing cytokines such as IL-12, IL-18 and IFN-γ, and may therefore be of value in developing vaccines for the neonate and the elderly. Extensive SAR studies led to the identification of C2-butyl furo[2,3-<i>c</i>]quinolone as an agonist with exquisite selectivity for human TLR8. Co-crystallization of this compound with the ectodomain of hTLR8 allowed a structure-based design of novel, TLR8-specific agonists. The availability of pure TLR8 agonists has, for the first time, allowed the comparison of ligand recognition and signaling in human and murine TLRs. Structure-activity relationships in novel classes of compounds, and immune correlates of adjuvanticity in in vivo models of immunization will be discussed.

Structure-based design of small molecule modulators of TLR8

249th National Meeting (2015)

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