D O Sviridov1, S K Drake2, L A Freeman3, A T Remaley3. 1. Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA. Electronic address: sviridovd@mail.nih.gov. 2. Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA. 3. Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA.
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.
ApoA-I mimetics are short synthetic n class="Chemical">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: Marcelo J A Amar; Wilissa D'Souza; Scott Turner; Stephen Demosky; Denis Sviridov; John Stonik; Jayraz Luchoomun; Jason Voogt; Marc Hellerstein; Dmitri Sviridov; Alan T Remaley Journal: J Pharmacol Exp Ther Date: 2010-05-19 Impact factor: 4.030
Authors: A T Remaley; J A Stonik; S J Demosky; E B Neufeld; A V Bocharov; T G Vishnyakova; T L Eggerman; A P Patterson; N J Duverger; S Santamarina-Fojo; H B Brewer Journal: Biochem Biophys Res Commun Date: 2001-01-26 Impact factor: 3.575
Authors: P Carvajal-Rondanelli; M Aróstica; C A Álvarez; C Ojeda; F Albericio; L F Aguilar; S H Marshall; F Guzmán Journal: Amino Acids Date: 2018-02-21 Impact factor: 3.520
Authors: Rafique M Islam; Mohsen Pourmousa; Denis Sviridov; Scott M Gordon; Edward B Neufeld; Lita A Freeman; B Scott Perrin; Richard W Pastor; Alan T Remaley Journal: Sci Rep Date: 2018-02-13 Impact factor: 4.379