Abstract
The importance of apolipoprotein A-I (apoA-I) in atherosclerosis was established by testing in animal models, and its potential usefulness in humans has been confirmed in preliminary studies. ApoA-I is a large protein comprising 243 amino acids, which means that venous administration is necessary. In addition, manufacture of apoA-I is difficult and expensive. Research has, therefore, been directed towards finding smaller peptide mimetics that produce similar results to apoA-I, but that are easier to manufacture and administer. The earliest peptides mimicked some of the lipid-binding properties of apoA-I but did not prevent atherosclerosis in mice. A detailed study of the physical–chemical characteristics of these peptides led to the realization that the hydrophobic region of the peptide was critical in determining bioactivity. A potent peptide, 4F, which was synthesized wholly from D-amino acids, could be given orally. Use of 4F significantly improved the function of HDL in mice and monkeys. When 4F was administered in combination with a statin, lesion size and macrophage content were reduced in mice with atherosclerosis, and lesions regressed in older mice. Vasoreactivity and endothelial sloughing were also improved in other rodent studies. Early human clinical trials are now being carried out on 4F. Here, we review the studies on apoA-I mimetic peptides that have been carried out so far.
Key Points
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A potent apolipoprotein A-I mimetic peptide, 4F, that could be given orally was synthesized wholly from D-amino acids
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Use of 4F significantly improved the function of HDL in mice and monkeys
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When administered in combination with a statin, atherosclerotic lesion size and macrophage content were reduced in mice and lesions regressed in older mice
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Vasoreactivity and endothelial sloughing were improved in a rat model of diabetes
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Early human clinical trials are in progress using D-4F
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Acknowledgements
This work was supported by NIH grants HL-30568 to AM Fogelman, HL-34343 to GM Anantharamaiah, and the Laubisch, Castera, and MK Grey Funds at UCLA to AM Fogelman.
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Mohamad Navab, GM Anantharamaiah and Srinivasa T Reddy are Principals and Alan M Fogelman is an Officer in BruinPharma, a start-up biotech company.
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Navab, M., Anantharamaiah, G., Reddy, S. et al. Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention. Nat Rev Cardiol 3, 540–547 (2006). https://doi.org/10.1038/ncpcardio0661
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DOI: https://doi.org/10.1038/ncpcardio0661
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