Protein mimics by attachment of cyclic peptides to molecular scaffolds

Abstract

The interaction between proteins is important in all biological functions. In practically every cellular process protein complexes have been identified as essential components. Defects or disturbance in the regulation of protein-protein interactions are responsible for many diseases. Therefore, the development of modulators of protein-protein interactions has become an important topic in drug design. Peptide-based mimics of protein binding sites are believed to be promising candidates for modulating protein-protein interactions. The binding sites of proteins consist of discontinuous epitopes. Mimicry of discontinuous epitopes is a challenging task because of the complex nature of these epitopes. In order to achieve good mimics, the multiple binding segments of the native protein should be combined into one single molecule by employing a molecular scaffold approach. Moreover, discontinuous epitopes are often present as loop-like structures. Therefore, it is believed that it is necessary to use cyclic peptides in discontinuous epitope mimicry. The aim of this thesis was the development of a general applicable method for the mimicry of discontinuous epitopes employing scaffolded cyclic peptides. Although the mimicry of discontinuous protein binding sites is gaining more and more interest, the design and synthesis of molecules, which are functionally capable of mimicking the epitopes of natural proteins, is still a great challenge. In addition, most examples of discontinuous epitope mimicry by scaffolded cyclic peptides concern bicyclic systems, only few approaches allow a regioselective attachment of more than two pre-organized ligands to a molecular scaffold. With respect to design and synthesis of scaffolded cyclic peptides mainly three issues are involved: 1) molecular scaffold, 2) cyclic peptides containing a handle for conjugation, 3) an efficient conjugation method for attaching the cyclic peptides to the scaffold. These topics were studied in this thesis.