Activation or inhibition of TLR4 by small molecules will provide in the next few years a new generation of therapeutics. TLR4 stimulation (agonism) by high-affinity ligands mimicking lipid A gave vaccine adjuvants with improved specificity and efficacy that have been licensed and entered into the market. TLR4 inhibition (antagonism) prevents cytokine production at a very early stage; this is in principle a more efficient method to block inflammatory diseases compared to cytokines neutralization by antibodies. Advances in TLR4 modulation by drug-like small molecules achieved in the last years are reviewed. Recently discovered TLR4 agonists and antagonists of natural and synthetic origin are presented, and their mechanism of action and structure-activity relationship are discussed.
Keywords: CD14; MD-2; TLR4; natural compounds; structure–activity relationship; synthetic compounds.