Use of the intestinal bile acid transporter for the uptake of cholic acid conjugates with HIV-1 protease inhibitory activity

Pharm Res. 1997 Feb;14(2):176-80. doi: 10.1023/a:1012044526054.


Purpose: To investigate the ability of the human intestinal bile acid transporter to transport cholic acid conjugates with potential HIV-1 protease inhibitory activity.

Methods: Cholic acid was conjugated at the 24 position of the sterol nucleus with various amino acids and amino acid analogs. The CaCo-2 cell line was used as a model to investigate the interaction of these bile acid conjugates with the human intestinal bile acid transporter. Interaction between the carrier and the conjugates was quantified by inhibition of taurocholic acid transport and confirmed by transport of radiolabelled conjugates in this cell line.

Results: The highest interaction with the transporter, as quantified by inhibition of taurocholic acid transport, occurred when a single negative charge was present around the 24 to 29 region of the sterol nucleus. A second negative charge or a positive charge significantly reduced the interaction. Transport of radiolabelled cholyl-L-Lys-epsilon-tBOC ester and cholyl-D-Asp-beta-benzyl ester was inhibited by taurocholic acid. Of all tested compounds, only cholyl-D-Asp-beta-benzyl ester showed modest HIV-1 protease inhibitory activity with an IC50 of 125 microM.

Conclusions: Cholic acid-amino acid conjugates with appropriate stereochemistry are recognized and transported by the human bile acid transporter and show modest HIV-1 protease inhibitory activity. Transport of these conjugates by the bile acid carrier is influenced by charge and hydrophobicity around the 24 position of the sterol nucleus.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Amino Acids / metabolism*
  • Amino Acids / pharmacology
  • Biological Transport
  • Caco-2 Cells
  • Carrier Proteins / metabolism*
  • Cholic Acids / chemistry
  • Cholic Acids / metabolism*
  • Cholic Acids / pharmacology
  • Epithelium / metabolism
  • HIV Protease / drug effects
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Hydroxysteroid Dehydrogenases*
  • Membrane Glycoproteins*
  • Sodium / pharmacology
  • Structure-Activity Relationship
  • Taurocholic Acid / metabolism*


  • Amino Acids
  • Carrier Proteins
  • Cholic Acids
  • HIV Protease Inhibitors
  • Membrane Glycoproteins
  • bile acid binding proteins
  • Taurocholic Acid
  • Sodium
  • Hydroxysteroid Dehydrogenases
  • AKR1C2 protein, human
  • HIV Protease