Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 195

They designed a-helical peptides, which were stabilized by two Glu-Arg
salt bridges on one side of the a-helix, while a b-cyclodextrin (anchored
through a 6-amino-6-deoxy group to a Glu side chain) was placed on the
other, as well as a Glu and a His. They prepared two of these hybrids with
different structural permutations, as well as two constructs lagging the
catalytic Glu. They studied the hydrolysis of the D - and L -enantiomers of
Boc-Phe-OpNP (pNP: 4-nitrophenyl) and observed a modest catalytic
activity by these trifunctional constructs. The authors further described
the synthesis of three a-helical 17-mer peptides functionalized with a
g-cyclodextrin and one or two pyrene units [83]. Two pyrene units can
be included in the cavity of a g-cyclodextrin and these peptides were
studied for their ability to dimerize.
Similarly, the Ueno group has also prepared four a-helical peptides
carrying a b-cyclodextrin and a dansyl (Dns) moiety as a model system for
molecular sensing [84]. Binding of guest compounds displaced the Dns
moiety from the b-cyclodextrin cavity, an event which could be followed
by fluorescence spectroscopy and circular dichroism spectroscopy.
In another design, a-helical peptides carrying b-cyclodextrin and two
naphthalene moieties were used to study binding of guests, as displace-
ment of one of the naphthalene groups from the cyclodextrin cavity could
be followed by excimer fluorescence [85]. This design could potentially
be used to detect molecules in aqueous solutions. These principles have
also been used in the design of two a-helical peptides carrying an
a-cyclodextrin as well as a pyrene and a nitrobenzene moiety as mole-
cule-responsive fluorescence sensors [86].
Finally, several groups have used anchoring of peptide chains through
the modified O-6 of cyclodextrin scaffolds as a means to improve the
pharmacological properties of peptides [75,87] and as an aid in drug
targeting [88].
Cyclodextrins are fascinating molecules with very interesting proper-
ties due to their central cavity, with its ability to bind guest molecules, and
the hydroxyls on the rims, which can be functionalized. Cyclodextrins are
likely to find numerous new applications, and new methods for their
derivatization will improve their utility. However, at present they have a
number of limitations: it is difficult to access cyclodextrins other than the
a- D -glucose-based a-, b- and g-cyclodextrins; it is nontrivial to modify the
central cavity; and the cyclic nature of these molecules has made it
difficult to differentiate between the different 6-OHs, which has limited
their use as structural elements in molecular architecture with peptides.
However, a procedure for the regioselective modification of benzylated
cyclodextrins has been reported [89].