Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 183

coworkers have described a glycopeptide antagonist of the leptin recep-
tor, where the carbohydrate moiety was expected to enhance penetration
of the blood-brain barrier [20].

5.5 CARBOHYDRATES AS SCAFFOLDS IN THE

DESIGN OF NONPEPTIDE PEPTIDOMIMETICS

In the early 1990s, Hirschmann, Smith, Nicolaou and coworkers
published a series of groundbreaking papers in which they described
the use of b- D -glucopyranosides as scaffolds in the design and synth-
esis of nonpeptidal peptidomimetics of the hormone somatostatin,
which led to the discovery of a partial somatostatin agonist [10,11].
This was one of the very first successful examples of de novo -designed
nonpeptidal peptidomimetics on a novel scaffold. Somatostatins are a
family of disulfide-bridged peptide hormones that are found in many
vertebrates and mammals, including humans (for a monograph, see
[21]; see also [22,23]). The tetradecapeptide somatostatin-14 (SST-14;
also referred to as somatotropin release-inhibiting factor (SRIF)-14) -
found in the central nervous system, pancreas, stomach, small intes-
tine and thyroid - inhibits the release of a number of hormones,
including growth hormone, glucagon and insulin [24-27]. The diverse
biological actions attributed to members of the somatostatin family
have been correlated to interactions with one or more of five receptor
subtypes, termed SSTR1-5 [28,29]. After this work by Hirschmann,
Smith, Nicolaou and coworkers these subtypes have been cloned, and
hypotheses have been developed about their respective functions [30].
The development of potent somatostatin variants that show selective
binding to each particular subtype is of interest in drug discovery
research.
Some cyclic hexapeptides, e.g. cyclo(Phe- D -Trp-Lys-Thr-Phe-Pro), had
been shown to be potent somatostatin agonists [31]. Here, the dipeptide
moiety Phe-Pro induces the side chains of the four other amino acids,
whichmakeuptheb-turn, to assume conformations which permit binding
and agonism. In addition, the Phe-Pro moiety provides a favourable
hydrophobic interaction with the SRIF receptor.
Hirschmann, Smith, Nicolaou and coworkers designed a SRIF
mimetic, starting from the relatively inflexible cyclic hexapeptide
cyclo(Phe- D -Trp-Lys-Thr-Phe-Pro), L -363,301, on a b- D -glucopyranoside
scaffold; b- D -glucopyranoside was chosen because of its well-defined