Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 159

parent peptide cyclo(-RGDfV-) and their retro sequences were
prepared and investigated [137]. One of the retroinverso analogue
cyclo(-VfdGr-) exhibited significantly reduced activity, although the
NMR-MD-based structure showed an almost identical side-chain
orientation, whereas the direction of the peptide bond was reversed.
This finding clearly gives evidence that at least one peptide bond
participates in the binding to the receptor. Other chemical modifica-
tions of the peptide bond such as thioamides or reduced amide bonds
often do not give satisfying conclusions, as these modifications usually
also result in conformational changes. Hence, the observed change
in biological activity cannot be unequivocally interpreted by the
substitution alone.
To further rigidify the conformation, different b-turn mimetics were
incorporated at the b-turn of the peptide, replacing D -Phe and Val.
Different classes of turn mimetics were chosen, including dipeptides,
peptide analogues and spiro compounds, as well as structures with planar
aromatic or carbohydrate cores.
It turned out that several of the b-turn mimetics do not substitute
a b-turn but are only allowed in the conformational space of b-turns
[139-144]. It is beyond the scope of this chapter to give details about
the different conformations and their activities for the integrin receptor
subtypes [136,140,141].
Many different modifications have been investigated, but the result of
an N-methyl scan yielded cyclo(-RGDf N MeVal-), which was chosen by
the Merck company as a drug candidate (Cilengitide) [138]. This peptide
has entered clinical phase III for the treatment of glioblastoma multi-
forme, metastatic prostate cancer and lymphoma (Figure 4.14).
Figure 4.14 Conformation of Cilengitide after a MD simulation [138] (see colour
Plate 3)