ApoA-I mimetic peptides promote pre-β HDL formation in vivo causing remodeling of HDL and triglyceride accumulation at higher dose.
Reverse cholesterol transport promoted by HDL-apoA-I is an important mechanism of protection against atherosclerosis. We have previously identified apoA-I mimetic peptides by synthesizing analogs of the 22 amino acid apoA-I consensus sequence (apoA-I(cons)) containing non-natural aliphatic amino acids. Here we examined the effect of different aliphatic non-natural amino acids on the structure-activity relationship (SAR) of apoA-I mimetic peptides. These novel apoA-I mimetics, with long hydrocarbon chain (C(5-8)) amino acids incorporated in the amphipathic α helix of the apoA-I(cons), have the following properties: (i) they stimulate in vitro cholesterol efflux from macrophages via ABCA1; (ii) they associate with HDL and cause formation of pre-β HDL particles when incubated with human and mouse plasma; (iii) they associate with HDL and induce pre-β HDL formation in vivo, with a corresponding increase in ABCA1-dependent cholesterol efflux capacity ex vivo; (iv) at high dose they associate with VLDL and induce hypertriglyceridemia in mice. These results suggest our peptide design confers activities that are potentially anti-atherogenic. However a dosing regimen which maximizes their therapeutic properties while minimizing adverse effects needs to be established.
Merck Research Laboratories, 126 East Lincoln Avenue, RY80Y-140, Rahway, NJ 07065, USA. ester_carballojane@merck.com
Ester
E
Carballo-Jane
Zhu
Z
Chen
Edward
E
O'Neill
Jun
J
Wang
Charlotte
C
Burton
Ching H
CH
Chang
Xun
X
Chen
Suzanne
S
Eveland
Betsy
B
Frantz-Wattley
Karen
K
Gagen
Brian
B
Hubbard
Marina
M
Ichetovkin
Silvi
S
Luell
Roger
R
Meurer
Xuelei
X
Song
Alison
A
Strack
Annunziata
A
Langella
Simona
S
Cianetti
Francesca
F
Rech
Elena
E
Capitò
Simone
S
Bufali
Maria
M
Veneziano
Maria
M
Verdirame
Fabio
F
Bonelli
Edith
E
Monteagudo
Antonello
A
Pessi
Raffaele
R
Ingenito
Elisabetta
E
Bianchi
D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry*; D053442:High-Density Lipoproteins, Pre-beta / Q000096:biosynthesis* / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000096:biosynthesis* / Q000378:metabolism
D016632:Apolipoprotein A-I; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; D014280:Triglycerides