The development of synthetic macrocycles represents a powerful approach toward
the identification of new protein binders or inhibitors of Protein-Protein Interactions
(PPI) which are known to play key biological roles in cancer signaling as well as in the regulation
of cell division cycle. Structural investigations led to identify “hot loops” sharing
common motifs that are mainly involved in PPIs. Most PPIs occur through large and flat
surfaces; currently these protein complexes are defined as “undruggable” by conventional
drug-discovery approaches, since the identification of small molecules to inhibit these targets
is often unreachable.
Typically macrocycles are 500-2000 Da in size, having 12-membered, or more, ring architecture: they do not
obey the Lipinski’s rule but, for them nature offers many examples as therapeutic agents such as erythromycin
(antibiotic), cyclosporin (immunosuppressant) and somatostatin (hormone).
Peptide-based macrocycles offer the advantages of directly mimicking secondary structures involved in PPIs
and their pharmacological application is related to the potential improvement of lead peptides in terms of potency,
selectivity, stability and cell permeation.
The promising relevance of cyclopeptides prompted to develop new synthetic methods for cyclization: often
biotechnological approaches as well as regioselective reactions have been employed to cyclize peptides rapidly
and nearly quantitatively. Moreover, different synthetic strategies in peptidomimetics’ macrocyclization are
actually available based on surrogate peptide bonds or NCL (Native Chemical Ligation) methods.
In this review we focus on the most common methods for the preparation of cyclopeptides and interesting applications
of the last decade.