Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 139

4.2.3 Chemical Modifications of Cyclic Peptides
There are numerous possibilities for chemical alterations of a cyclic
peptidic precursor molecule. Modifications retaining the peptide chain
include variation of amino acid stereochemistry and of the peptide strand
orientation. Other alterations are the introduction of small groups (e.g.
N-methylation of the peptide bond) or replacement of complete amino
acid building blocks by nonproteinogenic ones. Although all these mod-
ifications have been applied to linear peptides, they have quite a different
impact on cyclic molecules. When incorporated in peptidic cycles, the
entire backbone strand is influenced via its global connection, unlike a
linear compound, where just a local area is affected. An overview is given
in the following sections.
4.2.3.1 Peptide strand arrangements
The simplest modification, which is single substitution of natural L -amino
acids by D -enantiomers, usually has drastic effects on conformation and
biological activity. In linear peptides, a D -amino acid scan may provide
information on possible turn structures important for biological activity.
However, such a modification is hardly detectable (e.g. by NMR spectra)
as it only leads to a shift in the thermodynamical equilibriumof a very large
number of conformations. In cyclic peptides, the influence of a change in
stereochemistry on the conformation is much more pronounced, because
cyclization already results in a dramatic reduction in the number of distinct
conformations.
Complete substitution of all- L -amino acids by D -enantiomers leads
to inverso peptides, which lose their biological activity in most cases
[44,45]. A few exceptions are known where such peptides interact with
'achiral receptors'.
In retro peptides, the direction of the peptide bond and therefore the
primary sequence is reversed [46]. Similarly to inverso peptides, com-
pounds constructed in this way also lose their biological activity, as the
orientation of the amino acid side chains is different from the parent
peptide. To yield a comparable orientation of the side chains, the retro-
inverso concept was developed [47-51]. Here, the backbone chirality of
the amino acid building blocks of a retro peptide is changed (see
Figure 4.4). Neglecting the fact that - in relation to the template
structure - the backbone conformation could be influenced by this kind
of chemical alteration, retroinverso peptides exhibit their side chains in