β-Peptides as Inhibitors of Small-Intestinal Cholesterol and Fat Absorption

Selective lipid transport through the brush-border membrane in the small intestine of mammals is mediated by membrane-bound proteins, the so-called scavenger receptors of class B, type I or II (SR-BI or -BII). These, in turn, are inhibited by certain proteins and synthetic α-peptides that have an amphipathic helix as the binding motif (Fig. 1). In whole cells (test with human colonic carcinoma cells, CaCo-2), on the other hand, the inhibitors are subject to proteolysis. We have now tested six β-peptides (hexa-, hepta-, and nonamers 1 – 6), each carrying one to seven water-solubilizing side chains of either Ser or Lys, with a brush-border-membrane (BBM) vesicle model system (rate and IC50 values in Figs. 2 and 3) and with a tightly packed monolayer of CaCo-2 cells (rate in Fig. 4), to find that the rate of transport of cholesterol can be reduced to what may be considered the passive diffusion (`background') level. There is a correlation between the ability of the β-peptides to form an amphipathic-type 314-helical secondary structure in MeOH and their inhibitory effect (Table 1 and Fig. 5). Although the inhibitory activity of the β-peptides is in only the mM range (Table 2), it is to be compared with no activity at all of previously tested α-peptides and proteins (built of L-amino acids) in CaCo-2 cells. Furthermore, these active β-peptides (1, 5, and 6) contain only seven or nine residues and must be considered simple, first-generation models capable of mimicking the biological activity of amphipathic α-peptide helices in living whole cells.