Transport characteristics of peptides and peptidomimetics: II. Hydroxyethylamine bioisostere-containing peptidomimetics as substrates for the oligopeptide transporter and P-glycoprotein in the intestinal mucosa.
Peptide bond bioisosteres, such as hydroxyethylamine (Hea), have frequently been used to stabilize metabolically labile peptide bonds in peptidomimetic drug design in an effort to increase the oral bioavailability of drug candidates. However, the impact of the peptide bond bioisosteres on the cell permeation characteristics of peptidomimetics is not well understood, particularly with respect to the effects on the substrate activity for proteins that can restrict (e.g. P-glycoprotein, P-gp) or facilitate (e.g. the oligopeptide transporter, OPT) intestinal mucosal permeation of peptidomimetics. In this study, terminally free and terminally modified (N-acetylated and C-amidated) peptidomimetics of H-Ala-Phe-OH and H-Ala-Phe-Ala-OH with the Ala-Phe peptide bonds replaced by Hea bioisosteres were synthesized. Transport characteristics of these peptidomimetics were investigated using Caco-2 cell monolayers as an in vitro model of the intestinal mucosa. The study showed that the Hea bioisostere stabilized the peptidomimetics to protease metabolism in Caco-2 cells. All terminally free peptidomimetics showed significant affinity and substrate activity for OPT. The affinity and substrate activity for OPT were stereoselective for peptidomimetics containing an S,S-configuration for the two adjacent chiral centers related to the Hea bioisostere. Three of the four terminally modified peptidomimetics showed significant substrate activity for P-gp and, interestingly, the substrate activity for P-gp was also stereoselective; however, it was in favor of an R,R-configuration for the two adjacent chiral centers related to the Hea bioisostere.
Gao
J
J
Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence 66047, USA.
Winslow
S L
SL
Vander Velde
D
D
Aubé
J
J
Borchardt
R T
RT
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000588:Amines / Q000737:chemistry*; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism*; D005656:Fungal Proteins; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D026901:Membrane Transport Proteins; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000588:Amines; D002352:Carrier Proteins; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D009842:Oligopeptides