Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

•TLR4 activation and inhibition by small molecules has important pharmacological applications in the fields of vaccine adjuvants, antisepsis agents, and anti-inflammatory drugs.•The majority of simplified lipid A analogs so far developed that are active as TLR4 agonists or antagonists have saccharidic structures. We review here monosaccharide and disaccharide-based compounds.•These sugar-based compounds can be also classed according to their anionic or cationic character.•The mechanism of TLR4 inhibition by cationic compounds can be based on the stabilization of LPS aggregates or on the interaction with CD14 and MD-2.•Anionic compounds act by interacting with MD-2 and CD14 co-receptors.

A growing body of data suggests that therapies based on Toll-like receptors (TLR) targeting, in particular TLR4, holds promise in curing autoimmune and inflammatory pathologies still lacking specific treatment, included several rare diseases. While TLR4 activators (agonists) have already found successful clinical application as vaccine adjuvants, the use of TLR4 blockers (antagonists) as antisepsis agents or as agents against inflammatory diseases (including arthritis, multiple sclerosis, neuroinflammations) and cancer is still at a preclinical phase of development. This minireview focuses on recent achievements on the development of TLR4 modulators based on lipid A structure simplification, in particular on compounds having disaccharide or monosaccharide structures. As the TLR4 activity of natural TLR4 ligands (lipopolysaccharide, LPS and its biologically active part, the lipid A) depends on both the structure of endotoxin aggregates in solution and on single-molecule interaction with MD-2 and CD14 receptors, the rational design of TLR4 modulators should in principle take into account both these factors. In the light of the most recent advances in the field, in this minireview we discuss the structure–activity relationship in simplified lipid A analogs, with cationic or anionic amphiphilic structures.