Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 192

interesting that a Pd(II) conjugate with a thiol-functionalized cyclodex-
trin showed biomimetic peptidase activity at Xxx-Pro sites [69].
Here we should also mention that noncovalent interactions
between carbohydrates and peptides have been studied, e.g. binding of
b-cyclodextrin to the Alzheimer Ab(1-40) peptide at two sites [70].
Another noncovalent interaction is the insertion of functionalized cyclo-
dextrins into the cavity of bacterial pore-forming toxin, staphylococcal
a-hemolysin, which modulates the charge-selectivity of the transmem-
brane pore [71].
In an early work, Galons et al . prepared mono-(6-amino-6-deoxy-2,3-
di-O-methyl)-hexakis (2,3,6-tri-O-methyl)-b-cyclodextrin, in which a
single 6-OH in b-cyclodextrin had been substituted for an amino group
[67]. This derivative was obtained by introduction of a single 6-azido
group, followed by methylation of the 2,3-hydroxyls and finally reduc-
tion of the azide to give the amine. This monoamine derivative of
b-cyclodextrin was N-acylated with N a -Boc-protected amino acids or
Leu-enkephalin, which were subsequently deprotected (Figure 5.13) [72].

H-Tyr-Gly-Gly-Phe-Leu

NH

O

O

OCH 3

O

O

O

O

O

6

O

Figure 5.13 Leu-enkephalin-functionalized b-cyclodextrin [72]

In 1992, Di Blasio et al . reported a b-cyclodextrin derivative with
cyclo-(His-Pro), a diketopiperazine (DKP), covalently attached through
the side-chain imidazole to C-6 [73]. X-ray studies revealed that 6-deoxy-
6-cyclo(His-Leu)-b-cyclodextrin was in a 'sleeping swan'-like fold, with
the hydrophobic side chain of Leu nested inside the cavity of the macro-
cycle [73], i.e. with self-inclusion of the grafted molecule. Self-inclusion
(self-complexation) has also been observed in a tyrosinyl-cyclodextrin
conjugate, where the tyrosinyl moiety occupied the cyclodextrin cavity
[74]. In an attempt to improve the bioavailability of the highly d-opiod
receptor-selective disulfide-linked cyclic peptide [p-I-Phe 4 ]DPDPE, a
lead compound for the design of d-opiod analgesics, Hruby and
coworkers acylated per-O-methyl-derivatized mono-6-amino-6-deoxy-
b-cyclodextrin with [p-I-Phe 4 ]DPDPE [75]. The conjugate, per-O-methyl