CHAPTER 6: Molecular Tweezers and Clips that Modify Protein Function

Protein recognition by designed protein ligands is highly challenging, but bears great opportunities. Supramolecular chemists have recently been able to synthesize tailored ligands with remarkable protein recognition properties which are absent in the natural binding partners, and which lead to synergistic effects, positive cooperativity and exquisite selectivity. Thus, the combination of powerful charged interactions with hydrophobic forces has recently led to new prototypes of protein surface binders. This review summarizes the development of molecular tweezers (part 1) and clips (part 2) as unique tools for protein recognition. The parts begin with molecular tweezers for basic amino acid inclusion and the discovery of diphosphate clips for efficient cofactor binding, respectively. Gratifyingly, both host molecules complement each other due to their different molecular shapes. Molecular tweezers will be presented first in their interaction with amino acids and small disordered peptides, where they generally complex each Lys and Arg; then the review will proceed to tweezer complexation with protein surfaces, elucidating the preference for well-accessible basic residues and various examples of protein targeting and interference with protein–protein interactions. Finally, we discuss the advantages of additional recognition elements on the tweezer skeleton, which opens the door to numerous advanced applications in chemical biology and drug discovery. For the clips, we describe in detail the inclusion of two important cationic cofactors, followed by applications on cofactor-mediated enzymatic processes.