Modular synthesis-enabled mechanistic characterization of the potent antilipoperoxidant activity of peridinin

The peroxidation of polyunsaturated fatty acids is a hallmark of many human disorders, yet is has often remained ambiguous whether lipid peroxidation plays a causative and therefore addressable role in the onset or pathogenesis of a disease. Small molecule inhibitors of this oxidative process in theory possess the capacity to help clarify this ambiguity, but many of the currently available compounds have important limitations. We therefore proposed that context-specific selective pressures may have promoted the evolution of natural products with potent antilipoperoxidant activity in microorganisms that thrive in environments of extreme oxidative stress. Enabled by a modular building-block synthetic platform, the structurally atypical carotenoid peridinin was found to be a potent inhibitor of non-enzymatic bilayer lipid peroxidation. With the goal of maximizing the utility of peridinin as a small molecule probe of the role of lipid peroxidation in pathogenesis, the mechanistic underpinnings of its antilipoperoxidant activity were investigated. Solid-state NMR experiments with a site-selectively 13C-labeled peridinin isotopologue revealed that the potency is linked to a high effective molarity within lipid bilayers. In contrast to the primarily extramembranous localization of the less effective antilipoperoxidant astaxanthin, peridinin is completely embedded within and physically spans the hydrophobic core of lipid membranes. This antilipoperoxidant probe was leveraged in human primary endothelial cell and mouse model experiments to interrogate the contribution of membrane oxidation towards the pathogenesis of atherosclerosis and asthma. The peridinin-mediated mitigation of bilayer lipid peroxidation was shown to attenuate monocyte-endothelial cell adhesion, a key step in atherogenesis. Utilizing mouse models of acute asthma, we found that lipid peroxidation is alternatively not a key driver of the asthmatic phenotype. These results suggest that peridinin may have broad potential as a chemical probe to better understand the role of bilayer lipid peroxidation in human disease.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2018

Author dc:creator

• Haley, Hannah M.

Contributors dc:contributor

• Burke, Martin D.
• Denmark, Scott E.
• Imlay, James A.
• van der Donk, Wilfred A.

• carotenoid, lipid oxidation, atherosclerosis

Statement dc:rights

• Copyright 2018 Hannah Haley

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/101323

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/101323