There has been great interest in developing new therapies for atheroscleosis, particularly involving the modulation of high-density lipoproteins (HDL). We report the discovery of self-assembling amphiphilic cyclic peptides that bind and functionally modulate HDLs. The cyclic peptides remodel mature human plasma HDLs into lipid-poor HDLs, which are the initial acceptors of cholesterol in reverse cholesterol transport. Structure-activity relationship studies of the peptides suggest a unique sequence-dependent charge distribution and the requirement for peptide self-assembly processes in the mechanism of action. One of the peptides was found to be active in vivo (mice) in remodeling plasma HDLs for up to eight hours. In a two-week follow-up study involving daily oral administration of the peptide to mice fed a high-fat diet, total plasma cholesterol levels were reduced by greater than 50% compared to controls. Thus, cyclic peptides can serve as a new approach for developing supramolecular agents to treat lipid disorders.

Self-assembling cyclic peptide nanotubes for treating atherosclerosis

245th National Meeting (2013)

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