Document Type
Thesis
Degree
Master of Science
Major
Biochemistry & Biotechnology
Date of Defense
7-6-2017
Graduate Advisor
Dr. Nichols
Co-Advisor
Dr. Spilling
Committee
Dr. Nichols
Dr. Bashkin
Dr. Stine
Dr. Stine
Abstract
Systemic Inflammatory Response Syndrome (SIRS) is classified as an immune system response to an infectious state. If left untreated, SIRS leads to sepsis, septic shock, end-organ dysfunction, and death. As a patient progresses through these stages, associations of acute respiratory distress, disseminated intravascular coagulation, and acute renal failure persist, resulting in millions of deaths annually. Lipopolysaccharide (LPS), a bacterial endotoxin, is released into the blood stream, triggering SIRS. LPS is found in the outer cell-wall of Gram-negative bacteria and is responsible for initiation of a devastating cytokine storm. One of the regions of LPS, lipid A, is a polyacylated glucosamine disaccharide that is primarily responsible for the pathological response of the immune system. LPS interacts with a plasma-LPS binding protein (LBP) via the lipid A region. LPS-LBP signals the CD14 receptor found on phagocytes and Toll-like receptors (TLR4), which results in a signaling pathway for inflammatory molecules like cytokines, TNFα, among numerous others. Antibiotic treatments alone prove insufficient; with numerous research data indicating increased bacterial resistance.
It has been demonstrated that compounds resembling the lipid A region can act as antagonist to LPS signaling and would de-activate the inflammatory cascade. Blocking this cascade of events, in conjunction with other known sepsis treatments, would prove beneficial to patient prognoses. Lipid A analogues have been developed which are antagonists of LPS signaling and do not activate the inflammatory cascade. The most interesting antagonistsare the monosaccharides, which demonstrate that the glucosamine nitrogen can be replaced by oxygen and acyl groups can be replaced by more robust ethers.
OCLC Number
1040261902
Recommended Citation
Tipton, Christopher A., "Rational Drug Design Directed at Blocking the Initial Signaling Events in Lipopolysaccharide-Induced Sepsis." (2017). Theses. 305.
https://irl.umsl.edu/thesis/305
Included in
Biochemistry Commons, Biotechnology Commons, Immunoprophylaxis and Therapy Commons, Medicinal-Pharmaceutical Chemistry Commons, Molecular Biology Commons, Organic Chemistry Commons