Enhancement of Oral Drug Absorption - Effect of Lipid and Glycoside Conjugation on the Enzymatic Stability and Intestinal Permeability of IM862

IM862 is a naturally occurring thymic dipeptide L-Glu-L-Trp‚ which has been shown to possess immuno-modulating and anti-angiogenic properties1 and is currently under development for potential treatments 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 recent years, the conjugation of sugar moieties and lipoamino acids have been thoroughly investigated as a mean to enhance the stability towards enzymatic degradation and the permeability across biological membranes of peptides.2,3 In this rospect, a library of novel derivatives of the dipeptide IM862 was designed and synthesised by conjugating dodecanoic a-amino acid C12 ‚ and/or 1-amino-b-D-glucuronic acid GlcN‚, b-D-glucuronic acid Glc6‚ and N-D-glucopyranosylamine succinamic acid Gls‚ residues to the Glu-Trp scaffold, using an Fmoc solid-phase peptide synthesis strategy on trichlorotrityl resin