Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 181

relatively rigid structure to which amino acids, amino acid mimetics, side-
chain mimetics, peptides and so on can be attached. Thus, the carbohy-
drate scaffold can display substituents to control distance and geometry
between them. In this context, Hirschmann described nonpeptidal pepti-
domimetics with novel scaffolding [10,11]. In 1977, Walter had already
suggested that backbone amide elements might not be required for recep-
tor interaction and that a cyclic scaffold could be used [12]. Scaffolding
was used and proven in the 1980s, when Hirschmann described an
approach to the design of peptidomimetics, wherein the entire amide
backbone of a b-turn was replaced by novel scaffoldings devoid of
amide bonds or isosteric replacements (described in more detail in
Section 3.5) [10,11].
In summary, carbohydrates as scaffolds in peptide design can utilize a
range of structural features, including furanoid vs. pyranoid ring forms,
axial vs. equatorial orientation of hydroxyls, relatively rigid pyranoside
ring forms, regioisomeric hydroxyls, introduction of amino and carboxyl
groups, and monosaccharide vs. oligosaccharide (e.g. cyclodextrin) struc-
tures. Carbohydrates are thus candidates as mimetics for e.g. turns or
cyclic peptide structures and as templates for the control of the distance-
geometry of attached moieties.

5.4 GLYCOPEPTIDES

The chemistry of glycopeptide synthesis has been covered in extensive
reviews [1,13], and only a few general considerations shall be outlined
here. Glycopeptide synthesis was pioneered by H. Paulsen,
H. Kunz, M. Meldal, T. Norberg and others [13]. In the building-
block approach, the amino acid is glycosylated in solution and then
incorporated into the peptide, e.g. by solid-phase synthesis.
O-glycosidic linkages are generally acid-labile, but whereas they are
often stable enough to withstand treatment with trifluoroacetic acid
(TFA) at room temperature, HF will cleave most O-glycosidic bonds,
while N-glycosidic linkages from N-acetyl-glycosamines are generally
stable to HF. This makes solid-phase glycopeptide synthesis by a
9-fluorenylmethyloxycarbonyl (Fmoc) strategy the preferred approach;
upon completion of the synthesis, the final glycopeptide can be
released by TFA-containing 'cocktails' at room temperature. In the
glycosylation of the amino acid, it is most conveniently N a -Fmoc
protected, while the carboxylic acid can be masked as the