title: Mimicry of high-density lipoprotein: functional peptide-lipid nanoparticles based on multivalent peptide constructs.
abstract: We describe an approach for engineering peptide-lipid nanoparticles that function similarly to high-density lipoprotein (HDL). Branched, multivalent constructs, bearing multiple 23- or 16-amino-acid peptides, were designed, synthesized, and combined with phospholipids to produce nanometer-scale discoidal HDL-like particles. A variety of biophysical techniques were employed to characterize the constructs, including size exclusion chromatography, analytical ultracentrifuge sedimentation, circular dichroism, transmission electron microscopy, and fluorescence spectroscopy. The nanoparticles functioned in vitro (human and mouse plasma) and in vivo (mice) to rapidly remodel large native HDLs into small lipid-poor HDL particles, which are key acceptors of cholesterol in reverse cholesterol transport. Fluorescent labeling studies showed that the constituents of the nanoparticles readily distributed into native HDLs, such that the peptide constructs coexisted with apolipoprotein A-I (apoA-I), the main structural protein in HDLs. Importantly, nanolipid particles containing multivalent peptides promoted efficient cellular cholesterol efflux and were functionally superior to those derived from monomeric apoA-I mimetic peptides. The multivalent peptide-lipid nanoparticles were also remarkably stable toward enzymatic digestion in vitro and displayed long half-lives and desirable pharmacokinetic profiles in mice, providing a real practical advantage over previously studied linear or tandem helical peptides. Encouragingly, a two-week exploratory efficacy study in a widely used animal model for atherosclerosis research (LDLr-null mice) using nanoparticles constructed from a trimeric peptide demonstrated an exceptional 50% reduction in the plasma total cholesterol levels compared to the control group. Altogether, the studies reported here point to an attractive avenue for designing synthetic, HDL-like nanoparticles, with potential for treating atherosclerosis.
authors: Department of Chemistry, ‡Department of Immunology and Microbial Science, and §The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Yannan
authors: Y
authors: Zhao
authors: Tomohiro
authors: T
authors: Imura
authors: Luke J
authors: LJ
authors: Leman
authors: Linda K
authors: LK
authors: Curtiss
authors: Bruce E
authors: BE
authors: Maryanoff
authors: M Reza
authors: MR
authors: Ghadiri
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D010455:Peptides / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D011973:Receptors, LDL / Q000172:deficiency
chemical_list: D008075:Lipoproteins, HDL; D010455:Peptides; D011973:Receptors, LDL
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