Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 137

Figure 4.3 Different modes of cyclization for peptides. Left: conventional
cyclization. Right: backbone cyclization with all possible connections to backbone
amides; instead of the amide, a C a atom can be analogously connected
Another possibility for linking a linear peptide strand is the so-
called backbone cyclization. This method restrains the linear peptide
strand by inserting a bridge from a backbone amide nitrogen or a C a
carbon atom to any other position [43]. Such connections have the
advantage that the peptide chain termini remain free, which is impor-
tant for peptide hormones that are often found as N-terminal primary
amides, for example. However, it requires more synthetic effort than
conventional peptide cyclization, as unnatural amino acids are
incorporated.
Generally speaking, the actual problem is to find restraints that fix the
peptide into a conformation that is still recognized by the receptor
(matched case) [4]. In most cases the constraints cluster a molecule in a
family of conformations that does not contain the bioactive conformation
(mismatched case). This becomes plainly evident when comparing the
multitude of possible conformational families that represent mismatched
cases with the sparse amount of matched cases. This is analogous to a
jigsaw puzzle, where of the many similar pieces only one fits exactly in the
designated place.
4.2.2 Synthesis of Cyclic Peptides
In order to obtain cyclic peptides, sophisticated synthetic strategies
have been developed. The most common is head-to-tail cyclization of
linear precursors. The synthetic yields vary strongly with ring size,