1. A novel inhibitor of bacterial endotoxin derived from cinnamon bark
S Azumi, K Tanamoto, A Tanimura Biochem Biophys Res Commun . 1997 May 19;234(2):506-10. doi: 10.1006/bbrc.1997.6668.
A substance that inhibits the activity of bacterial endotoxin (LPS) was found in cinnamon bark. The inhibitor, extracted from dry cinnamon bark with 67% ethanol/water, was purified by using Limulus gelation activity as an indicator of endotoxin activity. The inhibitor suppressed the activity of the LPS when it was mixed with the inhibitor prior to the assay. The reduction of the LPS activity depended on the concentration of both the inhibitor and LPS when mixed, and also on the incubation time. The inhibitor suppressed the activity of all LPS and lipid A preparations tested regardless of the origin of the bacteria. The inhibitor alone did not affect the Limulus system. These results indicate that the inhibition was caused by direct interaction of the inhibitor with the LPS molecule. Furthermore the inhibitor abrogated the pyrogenicity of the LPS. Although it is uncertain whether the inhibitor actually plays a role in the defense mechanism in cinnamon bark, this is the first report that an inhibitor of bacterial endotoxin exists in a plant.
2. Endotoxin neutralizing peptides
Massimo Porro, Roman Jerala Curr Top Med Chem . 2004;4(11):1173-84. doi: 10.2174/1568026043388079.
Neutralization and sequestration of bacterial lipopolysaccharide which plays a key role in gram-negative sepsis is required to block the progression of sepsis at early stages in addition to destroying bacteria. Many of the host defense peptides which have antimicrobial activity are also able to bind to and neutralize LPS, however, these two activities do not necessarily correlate. Due to its toxicity application of polymyxin B as the prototype of LPS neutralizing peptide is limited to topical applications and extracorporeal removal of endotoxin. Development of novel endotoxin neutralizing peptides without the toxicity of polymyxin B have been based on the natural host defense peptides, fragments of LPS binding proteins and engineered peptides. Neutralization of LPS can be achieved through several different peptide fold motifs, which are reviewed in this article. Endogenous host defense peptides, fragments of endotoxin-binding proteins and synthetic anti-endotoxin peptides fold into alpha-helical, beta-hairpin, extended and compact conformations without regular secondary structure. In animal models many of the peptides have demonstrated good in vitro and in vivo endotoxin neutralizing activity but up to now none of the peptides has been approved for clinical application with an anti-endotoxin indication. Recent developments include preparation of novel types of endotoxin neutralizing compounds such as peptides modified by lipophilic moieties and non-peptidic molecules, particularly lipopolyamines and on the other hand additional medical applications such as extracorporeal endotoxin removal, targeting to inflammation sites or endotoxoid based vaccines.
3. Inhibition of endotoxin response by synthetic TLR4 antagonists
Lynn D Hawkins, Daniel P Rossignol, William J Christ Curr Top Med Chem . 2004;4(11):1147-71. doi: 10.2174/1568026043388123.
Endotoxin, from the outer membrane of Gram-negative bacteria, has been implicated as the etiological agent of a variety of pathologies ranging from relatively mild (fever) to lethal (septic shock, organ failure, and death). While endotoxin (also known as lipopolysaccharide or LPS) is a complex heterogeneous molecule, the toxic portion of LPS (the lipid A portion) is relatively similar across a wide variety of pathogenic strains of bacteria, making this molecule an attractive target for the development of an LPS antagonist. Research over the past fifteen years focused on the design of various lipid A analogs including monosaccharide, acyclic and disaccharide compounds has lead to the development of E5564, an advanced, unique and highly potent LPS antagonist. E5564 is a stable, pure LPS antagonist that is selective against endotoxin-mediated activation of immune cells in vitro and in animal models. In Phase I clinical trials, we have developed an ex vivo endotoxin antagonism assay that has provided results on pharmacodynamic activity of E5564 in addition to the more typical safety and pharmacokinetic evaluations. Results from these assays have been reinforced by analysis of in vivo antagonistic activity using a human endotoxemia model. Results from all of these studies indicate that E5564 is an effective in vivo antagonist of endotoxin, and may prove to be of benefit in a variety of endotoxin-mediated diseases. This review discusses the evolution of synthetic LPS antagonists with emphasis on the SAR and development of E5564 and its precursors.
