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Abstract
Grant Number: 1R01AI050107-01A2 Project Title: Rational Development of Endotoxin Sequestering Agents
PI Information: Name Title DAVID, SUNIL ABRAHAM. sdavid@ku.edu ASSISTANT PROFESSOR Abstract: DESCRIPTION (provided by applicant): 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.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
antigen antibody reaction, drug design /synthesis /production, endotoxin, lipopolysaccharide, septic shock, septicemia
binding site, blood protein, chemical binding, chemical structure function, cytokine, disease /disorder model, intermolecular interaction, neutralizing antibody
clinical research, fluorescent dye /probe, human subject, laboratory mouse, toxicant screening
Institution: UNIVERSITY OF KANSAS LAWRENCE 2385 IRVING HILL ROAD LAWRENCE, KS 660457568 Fiscal Year: 2003 Department: MEDICINAL CHEMISTRY Project Start: 01-MAY-2003 Project End: 30-APR-2007 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: BNP