Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 182

pentafluorophenyl (Pfp) ester. This serves a dual function as it is also
an 'activated ester' very suitable for the following coupling/acylation
step [14,15]. Other N- and C-protecting groups have been used with
success, as have derivatives with a free carboxylate [1,13]. Redesign of
naturally-occurring glycopeptides such as vancomycin will not be
covered here.
Introduction of glycosylation in a peptide also offers the prospect of
protection against proteolysis and improved aqueous solubility. A lead-
ing pharmaceutical example is the work to improve the poor solubility of
the potent, selective, conformationally-constrained tachykinin NK 2
receptor antagonist, MEN 10627, cyclo(Met-Asp-Trp-Phe-Dap-
Leu)cyclo(2b-5b) [16,17]. To overcome this problem, Quartara and
coworkers designed, among others, the bicyclic glycopeptide MEN
11420, which incorporates an amide linked N-acetyl- D -glucosamine
moiety (Figure 5.3). Indeed, the glycopeptide MEN 11420 proved to be
a potent and selective tachykinin NK 2 receptor antagonist [17].
Interestingly, the N-acetyl- D -glucosamine moiety did not produce major
changes in the affinity profile of the antagonist as compared to the analo-
gous nonglycosylated cyclopeptide MEN 10627; however, MEN 11420
showed significantly improved in vivo potency and duration of action.
Thus, Quartara and coworkers demonstrated the concept of glycosylation
of peptides as a means to improve ADME properties of peptides.
In a different approach, glycosyl-enkephalin conjugates have been
prepared to modulate the properties of enkephalin [18,19]. Otvos and
Figure 5.3 The Menarini glycopeptide MEN 11420 [16,17]