Toll-like receptors (TLRs) are a family of pattern recognition receptors on innate immune cells that recognize pathogen-specific components of microbial invaders. Among the TLRs, TLR4 is the specific sensor of lipopolysaccharide (LPS, endotoxin), one of the molecular components of Gram-negative outer membrane. LPS binds TLR4 and its accessory molecule MD-2 to form a stable TLR-MD-2 receptor complex, triggering an initial innate immune response which protects the host against a wide spectrum of unrelated pathogens. This defensive reaction includes secretion of inflammatory cytokines that activate natural killer cells and initiates a cascade of signals to cells of the adaptive immune arm, preparing them for the development of antigen-specific immune responses. In this regard, molecules capable of stimulating innate immunity can also act as adjuvants leading to enhanced antigen-specific immunity.<br/><br/>In the course of our own structure-activity studies on Lipid A, the active component of LPS, we have developed a new class of chemically stable synthetic monosaccharide compounds capable of eliciting robust innate and adaptive immune responses. This new class of TLR4 agonists encompasses a new monosaccharide scaffold, the Diamino Allose Phosphate (DAP), which contains a non-hydrolyzable 3-amide bond instead of the classical 3-ester bond present in Lipid A derivatives. This new series of DAPs is more potent than the known TLR4 agonists benchmarks MPL and GLA, and retains equivalent TLR4 activity to the corresponding known synthetic TLR4 agonists CRX-524 and CRX-601. In addition, these new TLR4 agonists have a much-improved stability when formulated in aqueous formulations. These new synthetic TLR4 agonists were shown to protect mice against a lethal influenza challenge and are potent vaccine adjuvants.

Development of novel synthetic TLR4 agonists

2019 Fall National Meeting

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