New Insight in LPS Antagonist

Lipopolysaccharide (LPS) or endotoxin, the major constituent of the outer membrane of Gram negative bacteria, has been implicated as the bacterial product responsible for the clinical syndrome of sepsis. LPS binding to the host receptor Toll-like receptor 4 (TLR4) triggers an inflammatory reaction characterised by the release of large number of inflammatory mediators that allow the host to respond to the invading pathogen. When this production becomes uncontrolled and excessive, it leads to the development of septic shock. Despite decades of efforts in supporting therapies, sepsis remains the leading cause of death amongst critically ill patients. Unfortunately, the major factor contributing to the high morbidity and mortality of sepsis is the lack of the effective targeted treatment. Indeed, over 30 drugs for the treatment of sepsis have been developed: many of these target specific inflammatory mediators and have thus been, in general, unsuccessful since sepsis relies on the cross talk of several cytokines and the block of a single factor has been proven to be ineffective. More successful strategies include those modulating the early phase of LPS signalling such as the ones that prevent the binding of LPS to host cells and the subsequent cascade of detrimental events. In this light, effective LPS antagonists would represent invaluable tools to efficaciously manage sepsis. This review discusses the evolution of naturally occurring and synthetic LPS antagonists with emphasis on the development of several natural new molecules.