Navab Mohamad, Anantharamaiah G M, Reddy Srinivasa T, Fogelman Alan M
Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Nat Clin Pract Cardiovasc Med. 2006 Oct;3(10):540-7. doi: 10.1038/ncpcardio0661.
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.
载脂蛋白A-I（apoA-I）在动脉粥样硬化中的重要性已通过动物模型试验得以确立，其在人类中的潜在效用也已在初步研究中得到证实。apoA-I是一种由243个氨基酸组成的大蛋白，这意味着必须通过静脉给药。此外，apoA-I的制造困难且成本高昂。因此，研究方向转向寻找能产生与apoA-I相似效果，但更易于制造和给药的更小的肽模拟物。最早的肽模拟了apoA-I的一些脂质结合特性，但并未预防小鼠的动脉粥样硬化。对这些肽的物理化学特性进行的详细研究使人们认识到，肽的疏水区域在决定生物活性方面至关重要。一种完全由D-氨基酸合成的强效肽4F可以口服。使用4F可显著改善小鼠和猴子体内高密度脂蛋白（HDL）的功能。当4F与他汀类药物联合使用时，可以减少动脉粥样硬化小鼠的病变大小和巨噬细胞含量，并且在老年小鼠中病变会消退。在其他啮齿动物研究中，血管反应性和内皮脱落情况也得到了改善。目前正在对4F进行早期人体临床试验。在此，我们综述了迄今为止对apoA-I模拟肽所开展的研究。
