Preface [Hot Topic: Endotoxin, Structure and Function: Promising Strategies for Combating Septic Shock (Guest Editor: Jurka Kidric)]

The initial systematic investigations of the toxic effects of putrescent material of plant and animal origin by Peter L. Panum (around 1856), led to the conclusion that the toxic principle originates from living microorganisms. Since then research on endotoxin, later defined as lipopolysaccharides (LPS), has become a major subject of immunological and immunochemical research. Great interest in LPS, the integral components of the cell wall of Gram-negative bacteria, stems from their manifold and diverse biological activities, their complex and unique physico-chemical properties, structural characteristics, serological properties and pathophysiological functions. Endotoxin is an extremely potent inducer of immune response. Already at extremely low concentrations it incites cellular responses and at higher concentrations can lead to sepsis and septic shock, a multiple organ dysfunction syndrome with high mortality that is particularly disturbing in intensive care units. However, depending upon the amount and route of introduction, LPS is also capable of producing beneficial effects in higher organisms by activating immune cells thus enhancing the capacity to cope with microbial infections and even tumors. Sepsis is a complex disease state depending on the patient history, the predisposition on the particular pathogen that a patient has been infected with, and the specific pathways activated in a patient that may lead to organ dysfunction. All these factors plus ambiguous diagnostic criteria defining sepsis make it difficult to determine the right treatment. The progress in successfully treating sepsis has been slow and costly. In recent years great strides have been made in the elucidation of the molecular basis of sepsis and thus providing new possibilities to combat sepsis and septic shock. This thematic issue of Current Topics in Medicinal Chemistry aims at presenting the state of art in endotoxin research with emphasis on the therapeutic potential promised by the basic knowledge of structures and molecular assemblies of the players in the molecular mechanisms involved in LPS recognition and neutralization of its toxic activity. The first contribution to this issue by S. H. Diks and co-workers describes the complexity of LPS signal transduction.The molecular mechanisms involved in the recognition of LPS and in the initiation of an immune response are discussed. Follows the review by K. Brandenburg and A. Wiese describing the relationships between the structure, function and activity of endotoxins. The unique structural features of LPS and the physico-chemical parameters important for the function of the outer membrane of bacterial cell wall are outlined. The inhibition of endotoxin response by synthetic TLR4 antagonists is extensively reviewed by D. P. Rossignol and coworkers. The authors discuss the evolution of LPS antagonists with emphasis on the SAR and development of E5564, an advanced and potent LPS antagonist that may prove to be of benefit in a variety of endotoxin-mediated diseases. R. Jerala and M. Porro are presenting an overview of endotoxin neutralizing peptides and recent developments in preparation of novel types of these compounds modified by lipophilic moieties and non-peptidic molecules, particularly lipopolyamines. They also present alternative applications of endotoxin binding peptides such as extracorporeal endotoxin removal and endotoxoid (the complex between Synthetic Anti-Endotoxin Peptides-SAEP and LPS) based vaccines against Neisseria meningitidis. The last contribution by P. Pristovsek and J. Kidric is concerned with the search for the molecular motifs of specific binding of LPS by anti-endotoxin proteins and peptides. The understanding of LPS mechanism of action at the atomic level is expected to provide leads for the development of new immunomodulatory compounds for the treatment of Gram-negative sepsis.