Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 86

thoseofasegmentofab-sheet about three residues long on each strand,
but also to about two turns of an a-helix. Moreover, the calixarene
scaffold allows the attachement of various substituents, which allow
creation of a hydrophilic and a hydrophobic surface, corresponding to
those found in amphipatic sheets or helices. Topomimetics of the anti-
angiogenic peptide anginex, which adopts an antiparallel b-sheet, were
developed (Figure 3.39), as were those of SC4, an a-helix-forming
bactericidal peptide, which displayed high potency [280,281].
Calixarenes functionalized with four cyclic peptides containing
the Gly-Asp-Gly-Tyr sequence were shown to have nM potency in
inhibiting PDGF (platelet-derived growth factor)-induced PDGFR
autophosphorylaton [282]. The analogue with Gly-Asp-Gly-Asp
sequence was able to block cytochrome c from binding to cytochrome
cperoxidase[283].

R'

R' R'

R'

N

NMe 2

R' = H, R =

K K K

O

K

N

R

NH 2

R' = tBu, R =

O

O O

O

R

R

R

R NH

Figure 3.39 Topomimetics of a b-sheet

3.4.2 Helix Mimetics

Helices are the predominant protein secondary structure. They are
important recognition motifs for protein-protein and protein-nucleic
acid interactions. Short peptide sequences, corresponding to these recog-
nition motifs, usually do not adopt a helical conformation. Several stra-
tegies have been developed to stabilize short peptides in a-helical
conformations, which include the use of unnatural amino acids such as
the a,a-dialkyl amino acids, and the introduction of noncovalent and
covalent side-chain constraints [284-286]. Also, foldamers, consisting of
oligomers of b, g, d-amino acids, vinylogous g-peptides or peptoids were
shown to form various kinds of helices [188,287,288]. Several helix
nucleating scaffolds and nonpeptidic scaffolds and modified peptide
backbones that mimic the recognition properties of a-helices have been
shown to lead to compounds with important biological properties. These
approaches have been reviewed recently [212,224,282,286,289,290].