Peptides are not generally orally active in part because of difficulties in crossing the biological barrier that lines the intestine. To address this, medicinal chemists have synthesized many peptide mimetics with novel therapeutic potential. These peptide mimetics contain bioisosteres of the peptide bond, which make them metabolically stable in vivo. However, because of their low permeability through biological barriers (e.g., intestinal mucosa) and their propensity to be cleared by the liver, oral dosage forms of peptide mimetics have been difficult to develop as therapeutic agents. Even when peptide mimetics are administered via a parenteral route (e.g., intravenous), they are, in general, rapidly cleared by the liver and tend not to gain access to important target areas (e.g., brain). In collaboration with Professor Ronald Borchardt of the Department of Pharmaceutical Chemistry at KU, we seek to elucidate the effects various peptide bioisosteres have on the permeability of peptide mimetics through biological barriers, such as the intestinal mucosa and the blood-brain barrier (BBB).
These objectives are addressed by preparing a variety of commonly used peptidomimetics – including our own "house brand" of ß-turn mimics – and measuring their transport properties using in vitro (i.e., cultured Caco-2 cells) methods developed in Professor Borchardt's laboratory. In this system, a monolayer of immortalized Caco-2 cells (derived from a human intestinal cancer cell line) is grown in a Transwell® system, where the cells differentiate normally to present one basolateral and one apical side. In addition, these cells express many of the important proteins involved in transport, such as the dipeptide transporter and the P-glycoprotein involved in multidrug resistance. Once the cells are grown and cultured, it is a simple matter to place the compound of interest on one side or another of the well and measure the kinetics of its transport to the other side.
References
1. Effect of Stereochemistry on the Transport of Aca-Linked ß-Turn Peptidomimetics Across a Human Intestinal Cell Line. Tamura, K.; Agrios, K. A.; Vander Velde, D.; Aubé, J.; Borchardt, R. Bioorg. Med. Chem. 1997, 5, 1859-1866.
2. Improvement of Oral Peptide Bioavailability: Peptidomimetics and Prodrug Strategies. Pauletti, G. M.; Gangwar, S.; Siahaan, T. J.; Aubé, J.; Borchardt, R. T. Adv. Drug Delivery Rev. 1997, 27, 235-256. A general review of the problems inherent in developing peptides as drugs.
3. A Functional Assay for Quantitation of the Apparent Affinities of Ligands of P-Glycoprotein in Caco-2 Cells. Gao, J.; Murase, O.; Schowen, R. L.; Aubé, J.; Borchardt, R. Pharm. Res. 2001, 18, 171–177.
4. Transport Characteristics of Peptides and Peptidomimetics: 2. Hydroxyethylamine Bioisostere-Containing Peptidomimetics as Substrates for the Oligopeptide Transporter and P-Glycoprotein in the Intestinal Mucosa. Gao, J.; Winslow, S. L.; Velde, D. V.; Aubé, J.; Borchardt, R. J. Peptide Res. 2001, 57, 316–329.
For More Information Contact:
Department of Medicinal Chemistry
4070 Malott Hall
Tel: 785-864-4495
FAX: 785-864-5326
Internet: jaube@ku.edu
