Table of Contents:

ApoA-I Mimetic Peptides

ApoA-I comprises a total of 243 amino acids and its secondary structure resembles 10 amphipathic α-helices that are crucial for its efficient interaction with lipids. Recently, there has been increasing interest in the application of peptides that resemble the amphipathic helices in apoA-I as therapeutic agents.

Anantharamaiah et al. synthesized the first apoA-I mimetic peptide, 18A, comprising 18 amino acids. Subsequently, several modifications to 18A have been made to create peptides that more closely mimic apoA-I in its antiatherogenic functions. For example, blocking the ends of 18A with an amide group and an acetyl group, thereby creating a peptide called 2 F, increased its helicity and efficiency in inducing cholesterol efflux (Venkatachalapathi et al. 1993; Yancey et al. 1995). In addition, tandem peptides composed of more than one amphipathic helix were shown to have a superior lipid affinity and ability to induce cholesterol efflux from macrophages compared to peptides that contain only one helix (Anantharamaiah et al. 1985; Garber et al. 1992; Wool et al. 2008). D'Souza et al. investigated the effect on cholesterol efflux and anti-inflammatory and antioxidant properties of 22 different bihelical apoA-I mimetic peptides. None of the compounds was superior in all antiatherogenic functions, and each of the examined antiatherogenic functions was shown to be primarily affected by specific structural features (D'Souza et al. 2010). These results indicate that apoA-I mimetic peptides more closely resembling apoA-I do not necessarily improve all various antiatherosclerotic functions. Moreover, combining several apoA-I mimetic peptides, each mimicking different structural aspects of apoA-I, may prove to be a valuable strategy to mimic the various anti-atherosclerotic properties of apoA-I.


Despite potent anti-inflammatory and antioxidant effects in vitro and in experimental models, the promise of 4 F in humans has not been a success to date (Navab et al. 2002, 2004). Two trials of 4 F in patients with CHD or at high risk of CVD assessed the effect of orally and parenterally administered 4 F on the HDL inflammatory index, a measure of HDL-mediated protection against LDL-induced monocyte chemotaxis, providing conflicting results (Bloedon et al. 2008; Watson et al. 2011). The development of 4 F by Novartis has subsequently been discontinued. Although a number of differences between the studies may partially account for the observed discrepancy, the primary outcome measure “HDL inflammatory index” has been proven to be largely irreproducible in the majority of laboratories. In fact, it has been difficult to identify an efficacy parameter for apoA-I mimetic peptides in human trials altogether, and in lack of standardization, all trials using HDL quality as readout have been disappointing.

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