Biomedical Engineering Reference
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resulted in numerous agonists. The question 'Can peptides be mimicked?'
[328] has certainly been given a positive answer in recent years. The
subject of nonpeptidic ligands for G-protein-coupled receptors and for
disrupting protein-protein interactions has been the topic of recent com-
prehensive reviews [212,224,282,289,327,329]. Some selected examples
which illustrate the power of the strategies discussed in the previous
sections will be discussed here.
One of the best examples of the hierarchical approach to peptidomi-
metic design is the case of somatostatin (or somatotropin release-inhibit-
ing factor, SRIF), where almost all of the previously discussed strategies
have been applied [330]. SRIF is a cyclic tetradecapeptide for which five
subtype receptors have been identified. Systematic studies resulted in the
development of the cyclic octapeptide octreotide (SMS 201-995) by
Sandoz and of the cyclic hexapeptide MK-678 (Seglitide) by Merck
[330,331] (Figure 3.43).
N
HN
NH
NH
O
O
O
O
O
O
O
O
NH
O
O
O
O
O
O
NH
2
NH
2
N
NH
2
HO
NH
HO
NH
HO
N
N
BnO
O
HO
NH
2
BnO
NH
2
HN
Figure 3.44 Glucose-, catechol and iminosugar-based somatostatin mimetics
A large number of analogues of these cyclic peptides have been pre-
pared, including a retroinverso cyclohexapeptide with 25% of the
potency of somatostatin [332] and N-peptoid analogues [333], resulting
in a spectrum of affinities and selectivities for the five subtype receptors.
All these studies indicated that the Phe-
D
-Trp-Lys-Thr tetrapeptide frag-
ment was the essential pharmacophore.
Conformational studies have shown that this fragment was maintained
in a type II
0
b-turn conformation by the remaining part of the cyclic
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