Over the past 20 years, medicinal chemists have synthesized many peptide mimetics (e.g., HIV protease inhibitors, glycoprotein (gp) IIb/IIIa receptor antagonists) with novel therapeutic indications (e.g., antiviral (AIDS), antithrombotic agents). These peptide mimetics contain structural features that stabilize them to hydrolytic pathways of metabolism and/or endow them with unique structural features that optimize their interactions with their macromolecular target (e.g., bioisosteres of amide bonds, turn mimetics). However, because of their poor biopharmaceutical properties (e.g., low permeation through the intestinal mucosa and high clearance by the liver), peptide mimetics often exhibit less than optimal oral bioavailability. Even when peptide mimetics are administered parenterally, they are in general rapidly cleared by the liver and tend not to gain access to important target areas (e.g., brain). Therefore, this research program is focused on elucidating what effects various amide bond bioisosteres and conformational constraints have on the permeation of peptide mimetics through the intestinal mucosa and the blood-brain barrier (BBB) and on their first pass clearance by the liver. Of particular interest are pathways that involve transporter proteins which either facilitate permeation across the intestinal mucosa (e.g., oligopeptide transporter) or restrict permeation across the intestinal mucosa and the BBB and facilitate clearance by the liver (e.g., multidrug resistance associated protein (MDR1) and multidrug resistance associated proteins (MRP1, MRP2)). The primary objectives of this research program for the next grant period are: (1) to elucidate the structure-transport relationships for a series of model peptide mimetics containing commonly used bioisosteres and conformational constraints with the efflux transporters (MDR1, MRP1, MRP2) and with the oligopeptide transporter; and (2) to determine what impact substrate activity for these transporters have on the in vivo biopharmaceutical properties of therapeutic peptide mimetics (e.g., HIV protease inhibitors, gpIIb/IIIa receptor antagonsits). The knowledge forthcoming from this research program should help medicinal chemists to rationally design peptide mimetics with improved biopharmaceutical properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM051633-05A1
Application #
2903190
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Haft, Carol Renfrew
Project Start
1994-09-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
1999-11-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Tang, Fuxing; Ouyang, Hui; Yang, Jerry Z et al. (2004) Bidirectional transport of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein, across MDCK-MDR1 cell monolayers. J Pharm Sci 93:1185-94
Horie, Kazutoshi; Tang, Fuxing; Borchardt, Ronald T (2003) Isolation and characterization of Caco-2 subclones expressing high levels of multidrug resistance protein efflux transporter. Pharm Res 20:161-8
Tang, Fuxing; Horie, Kazutoshi; Borchardt, Ronald T (2002) Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res 19:765-72
Tang, Fuxing; Horie, Kazutoshi; Borchardt, Ronald T (2002) Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res 19:773-9
Gao, J; Winslow, S L; Vander Velde, D et al. (2001) Transport characteristics of peptides and peptidomimetics: II. Hydroxyethylamine bioisostere-containing peptidomimetics as substrates for the oligopeptide transporter and P-glycoprotein in the intestinal mucosa. J Pept Res 57:361-73
Gao, J; Murase, O; Schowen, R L et al. (2001) A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells. Pharm Res 18:171-6
Gao, J; Sudoh, M; Aube, J et al. (2001) Transport characteristics of peptides and peptidomimetics: I. N-methylated peptides as substrates for the oligopeptide transporter and P-glycoprotein in the intestinal mucosa. J Pept Res 57:316-29
Sudoh, M; Pauletti, G M; Yao, W et al. (1998) Transport characteristics of peptidomimetics. Effect of the pyrrolinone bioisostere on transport across Caco-2 cell monolayers. Pharm Res 15:719-25
Li, J; Tamura, K; Lee, C P et al. (1998) Structure-affinity relationships of Val-Val and Val-Val-Val stereoisomers with the apical oligopeptide transporter in human intestinal Caco-2 cells. J Drug Target 5:317-27
Artursson, P; Borchardt, R T (1997) Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharm Res 14:1655-8

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