Inhibition of protein-protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads--and how criteria applied to these may differ from conventional small-molecule drugs--are summarized.

Photo-induced cross-linking (PIC) is a powerful strategy for generating information on biomolecular interactions. In PIC, the utility of traditional cross-linking methods is supplemented by the temporal control of photo-activation, enabling the study of non-covalent kinetic intermediates and heterogeneous mixtures. This tutorial review will introduce the photochemistry of activation, reactive intermediates, methods for the functionalisation of biomolecules and the installation of additional functionalities (e.g., affinity tags). In doing so, we shall illustrate the wealth of data that can be obtained using this approach, ranging from the identification of interacting partners and structural data to temporal information. Alongside a discussion of the strengths and weaknesses of the various approaches, their applicability to different types of biological system will be described.

Although many cellular processes depend upon enzymatic reactions, protein-protein interactions (PPIs) mediate a large number of important regulatory pathways and thus play a central role in disease development. In order to understand and selectively inhibit cellular signalling pathways, there is a pressing need for small molecules that target PPIs, particularly in the context of pharmaceutical development. This tutorial review will introduce the relevance of PPIs to chemical biology and highlight the key challenges in designing inhibitors. Some of the successes using conventional approaches to the identification of small-molecule PPI inhibitors will be highlighted, and also the reasons why these approaches have not always proven successful. Several general approaches tailored to particular protein topologies are emerging for the design of scaffolds that inhibit PPIs-these will form the major content of this review. Finally a summary of the challenges to be faced in developing inhibitors of PPIs into drug leads and how these challenges may differ from those encountered with enzyme-like targets will be given.

Hydrogen-bond-mediated non-covalent polymer synthesis is an emerging area that presents new opportunities for the design of stimuli-responsive materials. Central to this is the ready availability of appropriate building blocks with which to link monomers together. This review discusses recent developments in the design, synthesis and use of arrays of hydrogen-bonds as supramolecular linking units.