This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Based on conservative estimates, septicemia is associated with 200,000 human deaths annually in the United States. Morbidity and mortality rates are linked to the presence of endotoxin (lipopolysaccharide; LPS) in the blood of affected patients, strongly implicating endotoxemia as a critical factor in pathogenesis. LPS, a component of Gram-negative bacteria, is among the most potent proinflammatory substances known, initiating the production of multiple host-derived inflammatory mediators, including cytokines (e.g., TNF), arachidonic acid metabolites, and tissue factor. Data from our center indicate that structurally novel LPS from rhizobial nitrogen-fixing symbionts do not stimulate human monocytes and can significantly inhibit LPS-dependent TNF secretion by these cells. Due to its inherent variations in fatty acid acylation patterns, purified R. sin-1 lipid A cannot be developed as a therapeutic agent for Gram-negative septicemia. Furthermore, the microheterogeneity of rhizobial lipid A limits the identification of specific structural features that makes it an antagonist rather than an agonist. To address this problem, we have developed a flexible approach for the facile synthesis of a wide range of well-defined lipid A derivatives based on the structure of R. sin-1 LPS. A highly convergent strategy for the synthesis of several derivatives of the lipid A of R. sin-1 has been developed. The approach employed the advanced intermediate, which is protected in such a way that the anomeric center, the C-2 and C-2 amino groups and C-3 and C-3 hydroxyls can be selectively functionalized. The synthetic strategy was used for the preparation of lipid A derivatives, which contain an unusual octacosanoic acid moiety and differ in the oxidation-state of the anomeric center. The results of these biological studies indicate that the synthetic compounds lack the proinflammatory effects of E. coli LPS. Furthermore, a compound that contains an anomeric lactone emulated the ability of heterogeneous R. sin-1 LPS to antagonize enteric LPS, providing evidence for the critical role of the gluconolactone moiety of R. sin-1 LPS in mediating this antagonistic ef

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR005351-17
Application #
7358160
Study Section
Special Emphasis Panel (ZRG1-BNP (40))
Project Start
2006-02-01
Project End
2007-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
17
Fiscal Year
2006
Total Cost
$1,430
Indirect Cost
Name
University of Georgia
Department
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
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