beta-peptides as inhibitors of small-intestinal cholesterol and fat absorption

Selective lipid transport through the brush-border membrane in the small in testine of mammals is mediated by membrane-bound proteins, the so-called sc avenger receptors of class B, type I or II (SR-BI or -BII). These, in turn, are inhibited by certain proteins and synthetic alpha-peptides that have a n amphipathic helix as the binding motif (Fig. 1). In whole cells (test wit h human colonic carcinoma cells, CaCo-2), on the other hand, the inhibitors are subject to proteolysis. We have now tested six beta-peptides (hexa-, h epta-, and nonamers 1-6), each carrying one to seven water-solubilizing sid e chains of either Ser or Lys, with a brush-border-membrane (BBM) vesicle m odel system (rate and IC50 values in Figs. 2 and 3) and with a tightly pack ed monolayer of CaCo-2 cells (rate in Fig. 4), to find that the rate of tra nsport of cholesterol can be reduced to what may be considered the passive diffusion ('background') level. There is a correlation between the ability of the beta-peptides to form an amphipathic-type 3(14)-helical secondary st ructure in MeOH and their inhibitory effect (Table 1 and Fig. 5). Although the inhibitory activity of the beta-peptides is in only the mM range (Table 2), it is to be compared with no activity at all of previously tested alph a-peptides and proteins (built of L-amino acids) in CaCo-2 cells. Furthermo re, these active beta-peptides (1, 5, and 6) contain only seven or nine res idues and must be considered simple, first-generation models capable of mim icking the biological activity of amphipathic alpha-peptide helices in livi ng whole cells.