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H - Ala - Gly - Cys - Lys - Asn - Phe - Phe - Trp
HO - Cys - Ser - Thr - Phe - Thr - Lys
somatostatin-14
OH
O
O
H
3
C
N
N
N
H
H
H
2
N
H
3
C
S
N
O
O
O
O
O
O
H
O
O
H
S
HN
HN
N
N
N
H
N
H
HO
NH
2
O
NH
2
O
O
OH
OH
MK-678,Seglitide
Octreotide
Figure 3.43 Somatostatin-14 and reduced-size cyclic analogues
A 13 amino acid peptide binds to the oestrogen receptor in a helical
conformation. A head-on view of this coactivator peptide shows three
key leucine residues whose C
a
carbons are rougly positioned at the
corners of a triagle. A triazene scaffold was found to best mimic this
arrangement, and provided a coactivation binding inhibitor with mM
potency [326] (Figure 3.42).
As mentioned in Section 3.4.1.2, cyclic peptides with b-hairpin scaffold
Pro-
D
-Pro (Figure 3.33) were shown to mimic helical conformations of
the p53 peptide (see Figure 3.53) and of a Rev helical peptide [247,248].
Various nonpeptide helix mimetics have been discovered, mainly by
high-througput screening. A selection is shown in Figure 3.54, as ihibitors
of the p53/HDM2 interaction.
3.5
EXAMPLES OF PEPTIDOMIMETICS
The strategies that were discussed in the previous sections have been
applied to a variety of bioactive peptides, and have resulted in a large
number of modified peptides and peptidomimetics. Moreover, intense
screening efforts, followed by lead optimizations, have revealed a wealth
of new nonpeptide lead structures for peptide receptors [327]. For many
years, it was thought that the peptidomimetic approach would mainly
result in inhibitors of enzymes and antagonists of peptide receptors.
However, it is now clear that peptide mimicry by nonpeptides has also
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