Oral absorption enhancement of dipeptide L ‐Glu‐ L ‐Trp‐OH by lipid and glycosyl conjugation

In recent years, the conjugation of sugar moieties and lipoamino acids has been extensively investigated as a mean to enhance the stability towards enzymatic degradation and the permeability across biological membranes of poorly orally available drugs, including peptides. In this prospect, a library of novel derivatives of the dipeptide L ‐Glu‐ L ‐Trp, a naturally occurring thymic immunomodulator with high hydrophilic character and low membrane permeability, was designed and synthesised by conjugating 2‐amino‐dodecanoic acid (C 12 ) and/or 1‐amino‐β‐ D ‐glucuronic acid (GlcAN), β‐ D ‐glucuronic acid (GlcA) and N ‐β‐ D ‐glucopyranosylamine succinamic acid (GlsNS) residues to the Glu‐Trp scaffold, using an Fmoc solid‐phase peptide synthesis strategy on trichlorotrityl resin. A cellobiose derivative was also prepared in solution. The synthesized peptides showed no sign of toxicity to red blood cells at 200 μ M (haemolysis assay) and their resistance against enzymatic hydrolysis, assessed in Caco‐2 homogenates, was usually significantly increased, particularly for the C‐terminal conjugates. Several derivatives also saw their apparent permeability values greatly enhanced and one of the conjugates tested proved to be able to release the initial dipeptide after penetrating Caco‐2 monolayers. An initial in vivo experiment was then carried out in male Wistar rats to examine the effect of conjugation on the absorption rate and bioavailability. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 633–643, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com