Geoffrey Wool

Apolipoprotein A-I (apoA-I) mimetic peptides resemble the physiochemical properties of the helices of apoA-I and show promise for the treatment of atherosclerotic vascular diseases and other chronic inflammatory disorders. These peptides have numerous properties, such as the ability to remodel high-density lipoprotein, sequester oxidized lipids, promote cholesterol efflux, and activate an anti-inflammatory process in macrophages, any or all of which may contribute to their antiatherogenic properties. In murine models, the 4F peptide attenuates early atherosclerosis but seems to require the addition of statins to influence more mature lesions. A recently developed method for the oral delivery of the peptides that protects them from proteolysis will facilitate further research on the mechanism of action of these peptides. This review focuses on the properties of the 4F peptide, although numerous apoA-I mimetics are under investigation and a single "best" peptide that mimics ...

Modifying apolipoprotein (apo) A-I mimetic peptides to include a proline-punctuated alpha-helical repeat increases their anti-inflammatory properties as well as allows better mimicry of full-length apoA-I function. This study compares the following mimetics, either acetylated or biotinylated (b): 4F (18mer) and 4F-proline-4F (37mer, Pro). b4F interacts with both mouse HDL (moHDL) and LDL in vitro. b4F in vivo plasma clearance kinetics are not affected by mouse HDL level. Administration of biotinylated peptides to mice demonstrates that b4F does not associate with lipoproteins smaller than LDL in vivo, though it does associate with fractions containing free hemoglobin (Hb). In contrast, bPro specifically interacts with HDL. b4F and bPro show opposite binding responses to HDL by surface plasmon resonance. Administration of acetylated Pro to apoE(-/-) mice significantly decreases plasma serum amyloid A levels, while acetylated 4F does not have this ability. In contrast to previous reports that inferred that 4F associates with HDL in vivo, we systematically examined this potential interaction and demonstrated that b4F does not interact with HDL in vivo but rather elutes with Hb-containing plasma fractions. bPro, however, specifically binds to moHDL in vivo. In addition, the number of amphipathic alpha-helices and their linker influences the anti-inflammatory effects of apoA-I mimetic peptides in vivo.

Peptides that resemble in physicochemical properties the helices of apoprotein A-I, the major protein of atheroprotective HDL, show promise for the treatment of atherosclerosis-related vascular disease. The properties and promise of these so-called mimetic peptides will be explored in this review. Both HDL and mimetic peptides are able to scavenge and sequester oxidized lipids and hence protect endothelial cells and arteries from the pro-inflammatory action of oxidized LDL. Active mimetic peptides have an amphipathic alpha-helical secondary structure, whose hydrophobic face is particularly important for its bioactivity. The most frequently employed peptide is 4F. The comparative bioactivity of variants of 4F, particularly tandem helical peptides, has been explored. The recent observation of the very high affinity of bioactive peptides for oxidized fatty acids and phospholipids provides a likely mechanism for the action of these peptides in inhibiting early atherosclerosis formation. It is not clear that these peptides alone are effective in reversing established atherosclerosis, although they may achieve this outcome in synergy with statin therapy. Recent observations of mimetic peptides have pointed to promising therapies for patients with cardiovascular disease. The peptides appear to be well tolerated and effective in promoting the anti-inflammatory properties of HDL.