Lipopolysaccharides (LPS) or endotoxins are outer membrane constituents of gram-negative bacteria that play a key role in the pathogenesis of septic shock, a leading cause of mortality worldwide for which there is as yet no effective therapy. One possible approach to developing novel therapeutic strategies to treat sepsis is to sequester circulating LPS, a strategy that has been historically addressed using monoclonal antibodies directed against the structurally conserved lipid regions of LPS. However, a series of clinical trials using monoclonal antibodies have been unsuccessful owing to the lack of accessible recognition sites on the lipid. Our previous work on identifying structural requisites necessary for binding and neutralization of LPS in a variety of proteins, peptides and small molecules led to the identification of a novel class of structurally simple, nontoxic molecules, the lipopolyamines, which bind and neutralize LPS in vitro, and afford protection against LPS challenge in two murine models of gram-negative sepsis. Embodying an interdisciplinary approach, we propose to synthesize several homologous series of novel compounds rationally designed to maximize binding affinity and neutralization potency, and to exhibit desirable pharmacokinetic and toxicological profiles, based on optimal structural templates that we have already established with the lipopolyamines. Employing a hierarchical screening strategy, the interactions of these molecules with LPS will be comprehensively evaluated employing a variety of biophysical methods, including the determination of dissociation constants. Test compounds will be screened for the ability to inhibit LPS-induced cellular activation and production of key proinflammatory mediators of septic shock. Highly active molecules will be further tested in two murine models of gram-negative sepsis. The toxicity of the compounds will be systematically determined in a panel of in vitro assays.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Korpela, Jukka K
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University of Kansas Lawrence
Schools of Pharmacy
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Osaka, Ichie; Hefty, P Scott (2014) Lipopolysaccharide-binding alkylpolyamine DS-96 inhibits Chlamydia trachomatis infection by blocking attachment and entry. Antimicrob Agents Chemother 58:3245-54
Wu, Wenyan; Sil, Diptesh; Szostak, Michal L et al. (2009) Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines. Bioorg Med Chem 17:709-15
Nguyen, Thuan B; Kumar, E V K Suresh; Sil, Diptesh et al. (2008) Controlling plasma protein binding: structural correlates of interactions of hydrophobic polyamine endotoxin sequestrants with human serum albumin. Mol Pharm 5:1131-7
Nguyen, Thuan B; Adisechan, Ashok Kumar; Suresh Kumar, E V K et al. (2007) Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide. Bioorg Med Chem 15:5694-709
Bhattacharjya, Surajit; Domadia, Prerna N; Bhunia, Anirban et al. (2007) High-resolution solution structure of a designed peptide bound to lipopolysaccharide: transferred nuclear Overhauser effects, micelle selectivity, and anti-endotoxic activity. Biochemistry 46:5864-74
Sil, Diptesh; Shrestha, Anurupa; Kimbrell, Matthew R et al. (2007) Bound to shock: protection from lethal endotoxemic shock by a novel, nontoxic, alkylpolyamine lipopolysaccharide sequestrant. Antimicrob Agents Chemother 51:2811-9
Balakrishna, Rajalakshmi; Wood, Stewart J; Nguyen, Thuan B et al. (2006) Structural correlates of antibacterial and membrane-permeabilizing activities in acylpolyamines. Antimicrob Agents Chemother 50:852-61
Guo, Jian-Xin; Wood, Stewart J; David, Sunil A et al. (2006) Molecular modeling analysis of the interaction of novel bis-cationic ligands with the lipid A moiety of lipopolysaccharide. Bioorg Med Chem Lett 16:714-7
Miller, Kelly A; Suresh Kumar, E V K; Wood, Stewart J et al. (2005) Lipopolysaccharide sequestrants: structural correlates of activity and toxicity in novel acylhomospermines. J Med Chem 48:2589-99
Cromer, Jens R; Wood, Stewart J; Miller, Kelly A et al. (2005) Functionalized dendrimers as endotoxin sponges. Bioorg Med Chem Lett 15:1295-8

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