Enhancement of oral drug absorption—Effect of lipid conjugation on the enzymatic stability and intestinal permeability of l-Glu-l-Trp-NH2 Original Research Article

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-NH2 was investigated using enzymatic extracts and monolayers of Caco-2 cells, respectively. A series of eleven novel lipopeptide analogues of l-Glu-l-Trp-NH2 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.