title: Modulating LPS signal transduction at the LPS receptor complex with synthetic Lipid A analogues.
abstract: Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization.
authors.affiliation: Dextra Laboratories Ltd., Science and Technology Centre, Earley Gate, Reading, United Kingdom. Electronic address: aileen.white@dextrauk.com.
authors.forename: Aileen F B
authors.initials: AF
authors.lastname: White
authors.affiliation: Department of Chemistry and Biochemistry, University of Missouri-St. Louis, One University Boulevard, St. Louis, Missouri, USA. Electronic address: demchenkoa@msx.umsl.edu.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Demchenko
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D004731:Endotoxins / Q000737:chemistry; D006801:Humans; D007107:Immune System; D007249:Inflammation; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry*; D018950:Lipopolysaccharide Receptors / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000737:chemistry*; D051379:Mice; D008968:Molecular Conformation; D010766:Phosphorylation; D011485:Protein Binding; D018805:Sepsis / Q000188:drug therapy; D015398:Signal Transduction; D012995:Solubility; D013925:Thromboplastin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin
keywords: Endotoxin; Immune response; Inflammatory reactions; LPS receptor complex; Lipid A; Lipopolysaccharide; Mimetics; Sepsis; Toll-like receptor