Cyclopeptides are ubiquitously present in Nature. Their high physiological activity is often a result of the stabilization of certain bio-active conformations upon cyclization while the cyclic structure simultaneously protects against degradation by proteases.

Yet, cyclopeptides cannot only act as (small) substrates for (larger) receptors, the macrocyclic structure also allows them to serve as receptors for (smaller) guest molecules that can be bound inside the cavity. The natural cyclodepsipeptide valinomycin is a prominent example of such a receptor whose antibiotic activity is due to the ability to complex and transport potassium ions along bacterial cell membranes.

Although pioneering work on the development of cyclopeptide derived macrocyclic ligands was carried out in the group of E. Blout already between 1970 and 1990, the concept of using cyclopeptides as synthetic receptors in molecular recognition was not widely accepted in spite of the fact that cyclopeptide-based receptors possess various advantages with respect to macrocyclic receptors derived from, for example, crown ethers, calixarenes, or cyclodextrins. Specifically,

• cyclopeptides are structurally closely related to natural systems,
• their ring size is easily variable,
• they are prepared by sequential synthesis which allows for the introduction of various binding sites along the ring in a defined arrangement,
• their subunits can be varied in a wide range,
• and they are chiral.

These considerations motivated us to systematically study the host-guest chemistry of cyclopeptides. In this context, we concentrated on compounds containing natural and non-natural aromatic amino acid subunits in an alternating sequence along the ring with the rigid aromatic subunits mainly serving to reduce conformational flexibility.

We showed that such peptides are efficient synthetic receptors for cations and anions. Receptor affinity can be regulated by controlling the favored conformation in solution. While some peptides interact only with one component of an ion-pair, others are able to complex both ion-pair components simultaneously. The introduction of additional binding sites along the ring furnished host molecules for neutral guests, for example carbohydrates.

Our work thus clearly demonstrates the potential of such cyclopeptides as synthetic receptors and we expect a number of interesting applications for these compounds.