Abstract 13853: Biological Action of ABCA1 Ligand Peptide ATI-5261 and its Analogs With Improved Safety Features
Recent studies have produced apolipoprotein (apo) mimetic peptides that reduce substantial atherosclerosis in animal models when given orally, subcutaneously or intravenously in lipid-free form and composed of L-amino acids. These findings suggest small peptides may represent a viable approach for the treatment of acute coronary syndrome and atherosclerosis in humans. Despite these favorable features, several adverse effects have been noted in preclinical studies, including elevations in blood triglycerides (TG) and cytotoxic responses (ALT, AST and creatine kinase) at high doses. To address these issues, we established a screening paradigm involving >200 analogs of ATI-5261, a novel apoE mimetic peptide and ABCA1 ligand that stimulates cellular cholesterol efflux with high potency. Safety profiles of peptides were evaluated in mice and rats, and anti-atherosclerosis effects in apoE deficient (apoE-/-) mice fed high-fat western-diet (HFWD) for 14 weeks. These studies revealed the TG elevating effects and cytotoxic responses of class A a-helical peptides were governed by a different set of molecular determinants apart from those of ABCA1 mediated cholesterol efflux. A lead peptide (CS6253) emerged with improved safety features that retained the favorable drugability properties (i.e. solubility), potent and selective cholesterol efflux activity via ABCA1 (km= 0.26±0.14 vs. 0.25±0.04 uM for ATI-5261, respectively), and mediated high affinity binding to ABCA1 as well as produced nascent HDL similar to full-length apoA-I. In vivo CS6253 stimulated macrophage specific RCT and reduced (32%) substantial atherosclerosis in apoE-/- mice when administered (SQ or IP) at a dose of 30 mg/kg over 6 weeks. These structure-activity studies from lead optimization of the ATI-5261 peptide series provide new and exciting insights for improving the therapeutic potential of apo mimetic peptides.
- © 2013 by American Heart Association, Inc.