Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 184

conformation and equatorial orientations of the O-1-4 [11]. Their initial
target was a glucoside derivative, which carried an O-1 indole side chain
(Trp mimetic), an O-6 alkyl amine side chain (Lys mimetic) and 2,3,4-tri-
O-benzyl (Bn), in which the O-4 Bn could mimic Phe-Pro and the O-2 Bn
could mimic the other Phe. Similarly, they also prepared the 3-deoxy
analogue, which does not carry the 'superfluous' 3-O Bn, as well as a
whole range of other permutations. Computer modelling (MM2) showed
that a local minimum overlapped well with the bioactive conformation
of the cyclic hexapeptide. Considerable synthetic effort was required to
access these carbohydrate-based peptidomimetic, as depicted in

Figure 5.4.

O NH 2

O

BnO
BnO

O

NSO 2 Ph

BnO

Figure 5.4 Hirschmann's SRIF mimetic on a b- D -Glc p template; Bn, benzyl [11]

These peptidomimetics were tested in vitro in radioligand displace-
ment assays on membranes from subclones of the AtT-20 cell line using
different radiolabelled somatostatin analogues, as well as in other tests.
The compounds bound to the SRIF receptor in a dose-dependent manner
and with an affinity in the mM range, qualifying as SRIF agonists. The
results validated the claim that hydrogen-bonding to backbone amides is
not required for either binding or activation of the SRIF receptor.
However, only three of the four side chains in the b-turn of SRIF are
required for binding. The 2-O Bn moiety mimics Phe 7 and the 4-O Bn
moiety mimics Phe-Pro of the cyclic hexapeptide. The authors find that
the substituents mimic the interactions that were intended, but the indole
ring may contribute very little to binding, unlike the Trp residues in the
peptides. Hirschmann and Smith have suggested that b- D -glucose, and
more generally monosaccharides, could be privileged platforms for the
design of therapeutically important agents [32].
Inspired by the work of Hirschmann et al ., Murphy and coworkers
have prepared somatostatin mimetics with the iminosugar 1-deoxynojir-
imycin as a central scaffold [33]. 1-deoxynojirimycin is a nitrogen-
containing pyranoside and its secondary amine allows hydrogen binding
or chemical modifications.