Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 164

4.6 CONCLUSION
Cyclization of linear peptide strands improves their pharmacological
properties and makes them more druglike by reducing the accessible
conformational space. In particular, biostability is enhanced, as enzymes
that cleave linear peptides withinminutes do have significantly less points
of vantage for digestion. Additionally, cyclic peptides exhibit better
biological activity if their structures are fixed closer to the receptor-
bound conformation. The reduction in conformational flexibility also
causes receptor-subtype specificity and helps to suppress unwanted side
effects caused by promiscuous binding of linear peptides to whole recep-
tor families.
Apart from improving pharmacological properties, cyclization enables
rational drug design of peptides. Certain cyclic peptidic backbones have a
strongly preferred or even homogeneous 3D arrangement and can there-
fore be used as scaffolds to present amino acid side chains with their
pharmacophoric groups in a defined structure. The spatial screening
approach makes use of this rigidity to find the optimal presentation of
side chains by retaining the active peptide sequence but varying its con-
formation. The success of this simple procedure results from the fact that
recognition motifs in protein-protein (receptor-ligand) interactions are
often found in exposed loop regions, which are efficiently mimicked by
cyclic penta- and hexapeptides. Additionally, knowledge of the 3D struc-
ture of the active sequence enables (semi)rational design of peptidomi-
metics. Alternatively, the cyclic peptides obtained by spatial screening
can be further optimized to match the required pharmacological
properties.
Improvement of pharmacophoric properties, in combination with
rational design approaches, makes cyclic peptides interesting targets in
medicinal research; moreover, they have the potential to become success-
ful drugs like Cyclosporin A, Sandostatin or Integrilin.
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[3] R. Flaumenhaft, In: J. B. Taylor and D. J. Triggle, Chemical Biology in
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