Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 142

and cyclic peptides (see framed section in Figure 4.5). In an azapeptide,
the C a -proton moiety of a peptide is substituted by nitrogen, whereas in
peptoids the side chains of the amino acids are shifted to the amide
nitrogen. In both mimetics, the chiral information of the former C a is
lost, which may lead to global conformational changes in cyclic
peptides.
Peptide bond modifications are also present in natural products: oxazoles
and thiazoles have been found in non-ribosomally synthesized peptides. It is
obvious that such drastic changes have a strong impact on activity and
conformation. When incorporated in peptidic cycles, the entire backbone
strand is influenced, as opposed to a linear compound, where just a local
area is affected.
4.2.3.3 Amino acid side-chain alterations
The most commonly observed and utilized side-chain alteration is
cysteine bridging in cyclic peptides and proteins, which is easily formed
by oxidation of two thiol functions of the amino acid side chains.
Disulfide bonds help to stabilize the tertiary and quaternary structures
of proteins and also play an important role in constraining peptide con-
formations. However, the resulting cycles usually retain considerable
flexibility. In contrast to homodetic head-to-tail cyclized peptides, even
small peptides that contain a side-chain linkage are conformationally
inhomogeneous. For example, head-to-tail cyclized tetrapeptides exhibit
a strongly reduced conformational space, whereas a disulfide-bridged
tetrapeptide of the general structure CXYC (C: Cys; X,Y: any amino
acid) allows a multitude of conformations [61]. Although it is claimed in
the literature [62] that such Cys bridges stabilize b-turns, a simple com-
parison of published structures of b-turns [63] shows that the distance of
the b-carbons of the cysteine residues is too large to form a b-turn when
they are bridged by a disulfide bond. Hence, standard b-turns cannot be
formed in such structures. Another drawback of disulfide bonds is their
easy reductive cleavage under many physiological conditions, e.g. in the
cytosol.
A further obvious way to cyclize linear peptide strands is linkage via
amide bonds between carboxylic and amine functionalities. Such connec-
tions are also found in many natural and unnatural amino acids.
In principle, all kinds of feasible chemical modifications could be intro-
duced for cyclization. However, much higher synthetic efforts are neces-
sary because not only the functionalities themselves have to be built, but