Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 136

brush border membrane of the gut must be achieved. Furthermore,
paracellular (via tight junctions) or transcellular uptake is required.
For some compounds, for instance di- or tripeptides, active transporters
exist (e.g. the peptide transporter PEPT1 [39]), which could hypotheti-
cally be exploited as a natural 'transmission machinery'. So far, only
cyclic peptides with multiple N-methylations such as cyclosporin A are
orally available to a great extent. Therefore, it might be possible
that cyclization of peptide templates in combination with alterations
like N-methylation will allow control of biological activity, selectivity,
stability and bioavailability.
In the following sections, the widespread effects of cyclization on
peptides with respect to druglike properties are discussed. After treating
the basic concepts underlying peptide cyclization and the synthetic path-
ways for generating such compounds (Section 4.2), conformational and
dynamic features of cyclic peptides are illustrated (Section 4.3).
Moreover, strategies for the (semi)rational design of cyclic and modified
peptide drug candidates are presented (Section 4.4). Finally, three cases of
successful design of cyclic peptides with high medicinal potential are
given (Section 4.5).
4.2 PEPTIDE CYCLIZATION
4.2.1 Possibilities of Peptide Cyclization
Biologically active, linear peptide sequences are mostly derived from
parts of proteins or by screening of synthetic libraries prepared on solid
phase. In addition, epitope mapping, sequence comparison between dif-
ferent binding proteins, structural consideration, phage display or pep-
scan methods provide promising peptidic templates [40,41]. Alternatively,
natural products that show the desired pharmacological effects can serve as
a starting point for further optimization. Usually templates are found
which exhibit a reasonable to good binding affinity but often lack the
pharmacological properties like specificity and stability.
There are different ways to cyclize peptides. The linear peptide
strand can be cyclized not only from head to tail, connecting the C-
and N-termini, but also by linking to amine and carboxylic functions in
amino acid side chains, giving side-chain-to-head or side-chain-to-tail
connections. Side-chain-to-side-chain bridges have also been described
(Figure 4.3) [42].