title: Amphipathic polyproline peptides stimulate cholesterol efflux by the ABCA1 transporter.
abstract: ApoA-I mimetics are short synthetic peptides that contain an amphipathic α-helix and stimulate cholesterol efflux by the ABCA1 transporter in a detergent-like extraction mechanism. We investigated the use of amphipathic peptides with a polypro helix for stimulating cholesterol efflux by ABCA1. Polypro peptides were synthesized with modified prolines, containing either a hydrophobic phenyl group (Prop) or a polar N-acetylgalactosamine (Prog) attached to the pyrrolidine ring and were designated as either PP-2, 3, 4, or 5, depending on the number of 3 amino acid repeat units (Prop-Prog-Prop). Based on molecular modeling, these peptides were predicted to be relatively rigid and to bind to a phospholipid bilayer. By CD spectroscopy, PP peptides formed a Type-II polypro helix in an aqueous solution. PP-2 was inactive in promoting cholesterol efflux, but peptides with more than 2 repeat units were active. PP-4 showed a similar Vmax as a much longer amphipathic α-helical peptide, containing 37 amino acids, but had a Km that was approximately 20-fold lower. PP peptides were specific in that they did not stimulate cholesterol efflux from cells not expressing ABCA1 and were also non-cytotoxic. Addition of PP-3, 4 and 5 to serum promoted the formation of smaller size HDL species (7 nM) and increased its capacity for ABCA1-dependent cholesterol efflux by approximately 20-35% (p < 0.05). Because of their relatively small size and increased potency, amphipathic peptides with a polypro helix may represent an alternative structural motif for the development of apoA-I mimetic peptides.
authors.affiliation: Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA. Electronic address: sviridovd@mail.nih.gov.
authors.forename: D O
authors.initials: DO
authors.lastname: Sviridov
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Drake
authors.affiliation: Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Freeman
authors.affiliation: Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood*; D006224:Cricetinae; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D010455:Peptides; C011083:polyproline; D002784:Cholesterol
keywords: ABCA1; Cardiovascular disease; Cholesterol; Peptides; Polypro