title: Enhancement of oral drug absorption-effect of lipid conjugation on the enzymatic stability and intestinal permeability of l-Glu-l-Trp-NH(2).
abstract: The dipeptide l-Glu-l-Trp-OH (IM862) is currently under development for the treatment of certain cancers and immuno-deficiency disorders. However, due to its highly hydrophilic character, IM862 demonstrates low permeability across biological membranes, including the gastro-intestinal track, which makes it not orally available. In this study, the effect of lipid conjugation on the stability and intestinal permeability of the IM862 amide derivative l-Glu-l-Trp-NH(2) was investigated using enzymatic extracts and monolayers of Caco-2 cells, respectively. A series of eleven novel lipopeptide analogues of l-Glu-l-Trp-NH(2) was synthesized using tert-butyloxycarbonyl or 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis. In vitro assays demonstrated an improved stability to proteolytic enzymes and increased intestinal permeability for several conjugates, thereby supporting the hypothesis that lipidation may provide a means to enable the oral administration of IM862.
authors.affiliation: School of Molecular and Microbial Sciences (SMMS), The University of Queensland, St. Lucia, Qld 4072, Australia.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Bergeon
authors.forename: Istvan
authors.initials: I
authors.lastname: Toth
mesh_terms: D000284:Administration, Oral; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004795:Enzyme Stability; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D008055:Lipids / Q000737:chemistry*; D008968:Molecular Conformation; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D004151:Dipeptides; D008055:Lipids; C060736:thymogen