Structure and function of HDL mimetics

Abstract

HDL mimetics have been constructed from a number of peptides and proteins with varying structures, all of which bind lipids found in HDL. HDL mimetics containing a peptide or protein have been constructed with as few as 4 and as many as 243 amino acid residues. Some HDL mimetics have been constructed with lipid but without a peptide or protein component. Some HDL mimetics promote cholesterol efflux, some have been shown to have a remarkable ability to bind oxidized lipids compared to human apolipoprotein A-I (apoA-I). Many of these peptides have been shown to have antiinflammatory properties. Based on studies in a number of animal models and in early human clinical trials, HDL mimetics appear to have promise as diagnostic and therapeutic agents.

Figure 1. The 4F peptide when synthesized from L-amino acids undergoes degradation after injection

40,000 dpm of ¹⁴C-L-4F (specific activity 4mCi/mg peptide) was injected intravenously into a wild-type C57BL/6 mouse. The mouse was bled at the indicated time points and the plasma was fractionated by FPLC and the cholesterol content of the fractions determined (data not shown) and the radioactivity in the fractions counted and graphed as shown in the Figure. The HDL-containing fractions and the post-HDL fractions were then analyzed by reverse phase HPLC and the results were confirmed by mass spectrometry. Intact ¹⁴C-L-4F was found in the HDL-containing FPLC fractions. No intact ¹⁴C-L-4F was found in the fractions eluting after the HDL-containing fractions at any time point.

Figure 2. The 4F peptide significantly reduced serum amyloid A (SAA) levels in the plasma of apoE null mice

The 4F peptide synthesized from all L-amino acids was injected subcutaneously at a dose of 1 mg/kg into apoE null mice (n = 19) or the mice were injected with the vehicle alone (n = 14). Six hours later the mice were bled and serum amyloid A (SAA) levels in plasma were determined by ELISA. The values shown are Mean ± SD; *p = 0.0317.