Invading pathogens are controlled by the innate and adaptive arms of the immune system. While adaptive immunity, mediated by B and T lymphocytes, often takes some time to develop, the first line defense is provided by innate immunity. Such initial rapid response is mediated by a group of proteins called “pattern recognition receptors” (PRR) by detecting the presence of structural motifs known as “pathogen-associated molecular patterns” (PAMP) on the surface of the pathogens. Recent evidence has shown that the family of Toll-like receptors (TLR) plays a major role in this innate immune recognition. PAMPs can be protein, lipid, nucleic acid, and carbohydrate, including lipopolysaccharide, CpG DNA, dsRNA, lipoteichoic acid, peptidoglycan, lipoarabinomannans, lipopeptide, and choline-containing phosphoglycolipids. Binding of TLRs to their ligands on invading pathogens induces the production of reactive oxygen and nitrogen intermediates (ROI and RNI), pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. It is currently believed that TLRs play a critical role in linking the innate and adaptive immunity.

It is well recognized that some of these PAMPs are strong immune stimulants and/or modulators. While these natural ligands are structurally very complicated and often accompany with undesirable toxicity in humans, direct application of these molecules in pharmaceutical industry is very limited. With increasing structural information emerging from current research in Toll-like receptors and innate immunity, rational design of synthetic ligands targeting these receptors has become an attractive and feasible task to mimic the biological functions of these naturally occurring macromolecules. In addition, structurally well-defined synthetic TLR ligands will provide useful tools to understand the molecular details of receptor-ligand binding and the signaling mechanisms involved in TLR-mediated immune activation.