Novel Agents that Prevent Atherosclerosis: Multivalent Peptide Constructs and Self-Assembling Cyclic DL-α-Peptides
Peptides 2015, Proceedings of the 24th American Peptide Symposium(2015)
Abstract
Heart disease is the number one killer worldwide, and is responsible for nearly a third of all deaths in the USA. The principal cause of heart disease is lipid accumulation in the arteries with attendant deposition of atherosclerotic plaque, which is comprised mainly of lipids, cholesterol, calcium salts, cells, and cellular debris. Atherosclerosis can be treated by reducing low-density lipoproteincholesterol (LDL-C) via administration of statin drugs. High-density lipoproteins (HDLs) appear to protect against atherosclerosis, such that an increase in their levels and function is desirable. HDL particles, ranging in size from 7-13 nm, are in a constant state of dynamic flux, where the large particles convert into smaller particles, or release free apoA-I. HDL particles accept cholesterol and lipids from peripheral cells and plaques for elimination in the liver (Reverse Cholesterol Transport). The antiatherogenic action of HDL is related to the major structural protein, apolipoprotein A-I (apoA-I), a 243-mer in humans that is comprised of 10 amphiphilic -helices [1]. ApoA-I mimetic peptides are generally amphiphilic -helices that can boost levels of cholesterol-mobilizing, HDL-like particles or improve the functional properties of such particles [1]. We have been involved in the design, synthesis, and functional characterization of novel molecules that mimic apoA-I based on the multivalent presentation of 23-mer and 16-mer amphiphilic, α-helical peptides [2]. Some of these derivatives were athero-preventive in a key mouse model on i.p. and oral (!) administration [3]. Results from this work led us to explore amphiphilic cyclic DL--peptides that could self-assemble into amphiphilic nanotubes.
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Key words
prevent atherosclerosis,multivalent peptide constructs,self-assembling
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