Controlling plasma protein binding: structural correlates of interactions of hydrophobic polyamine endotoxin sequestrants with human serum albumin.

Hydrophobically substituted polyamine compounds, particularly N-acyl or N-alkyl derivatives of homospermine, are potent endotoxin (lipopolysaccharide) sequestrants. Despite their polycationic nature, the aqueous solubilites are limited owing to the considerable overall hydrophobicity contributed by the long-chain aliphatic substituent, but solubilization is readily achieved in the presence of human serum albumin (HSA). We desired first to delineate the structural basis of lipopolyamine-albumin interactions and, second, to explore possible structure-activity correlates in a well-defined, congeneric series of N-alkyl and -acyl homospermine lead compounds.

Structural correlates of antibacterial and membrane-permeabilizing activities in acylpolyamines.

A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity.

Anti-endotoxin agents. 3. Rapid identification of high-affinity lipopolysaccharide-binding compounds in a substituted polyamine library.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are an integral part of the outer leaflet of the outer-membrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis.

Structure-activity relationships in lipopolysaccharide neutralizers: design, synthesis, and biological evaluation of a 540-membered amphipathic bisamide library.

Lipopolysaccharides (LPS), also called "endotoxins", are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. We had earlier shown that small molecules bind and neutralize LPS if they contain (i) two protonatable cationic groups separated by a distance of approximately 14 A to facilitate interactions with the phosphate moieties on the lipid Angstrom component of LPS and (ii) a long-chain aliphatic hydrocarbon to promote hydrophobic interactions.

Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.

We have shown that lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities.

Molecular modeling analysis of the interaction of novel bis-cationic ligands with the lipid A moiety of lipopolysaccharide.

Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer-membrane constituents of Gram-negative bacteria and play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. We have shown that the pharmacophore necessary for optimal recognition and neutralization of LPS by small molecules requires an interaction between two protonatable positive charges separated by a distance of approximately 14A, which corresponds to the distance between two anionic phosphates on the glycolipid component of LPS called lipid A. The in silico binding of a diverse set of compounds with bis-amino, -amidino, -guanidino, and -aminoguanidino functionalities, identified as potential lead scaffolds in a high-throughput screen, with lipid A was explored using molecular docking simulations.

Lipopolysaccharide sequestrants: structural correlates of activity and toxicity in novel acylhomospermines.

Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time.

Lysine-spermine conjugates: hydrophobic polyamine amides as potent lipopolysaccharide sequestrants.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time.

Functionalized dendrimers as endotoxin sponges.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. Polyamidoamine dendrimers, with the surface amines substoichiometrically derivatized with alkyl groups bind LPS with high affinity, neutralize LPS-induced inflammatory responses in vitro, and afford protection in a murine model of endotoxic shock.

Anti-endotoxin agents. 2. Pilot high-throughput screening for novel lipopolysaccharide-recognizing motifs in small molecules.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are an integral part of the outer leaflet of the outer-membrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis.

Anti-endotoxin agents. 1. Development of a fluorescent probe displacement method optimized for the rapid identification of lipopolysaccharide-binding agents.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time.

Side-chain-to-tail thiolactone peptide inhibitors of the staphylococcal quorum-sensing system.

The expression of many staphylococcal virulence factors are regulated by the agr locus via a two-component signal transduction system (TCSTS), which is activated in response to a secreted autoinducer peptide (AIP). By exploiting the unique chemical architecture of the naturally occurring AIP-1, several potent inhibitors of staphylococcal TCSTS were designed and synthesized using either a linear or branched solid-phase approach. These inhibitors are competitive binders and contain the crucial 16-membered side-chain-to-tail thiolactone peptide pharmacophore.