Stapled peptides are a promising class of alpha-helix mimetic inhibitors for protein–protein interactions. We report the divergent synthesis of “functionalised” stapled peptides via an efficient two-component strategy. Starting from a single unprotected diazido peptide, dialkynyl staple linkers bearing different unprotected functional motifs are introduced to create different alpha-helical peptides in one step, functionalised on the staple linkage itself. Applying this concept to the p53/MDM2 interaction, we improve the cell permeability and p53 activating capability of an otherwise impermeable p53 stapled peptide by introducing cationic groups on the staple linkage, rather than modifying the peptide sequence.

Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.

Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.

Chemical genetics can be defined as the study of biological systems using small molecule tools. Cell permeable and selective small molecules modulate gene product function rapidly, reversibly and can be administered conditionally in either a cellular or organismal context. The small molecule approach provides exacting temporal and quantitative control and is therefore an extremely powerful tool for dissecting biological processes. This tutorial review has been written to introduce the subject to a broad audience and highlights recent developments within the field in four key areas of biology: modulating protein–protein interactions, malaria research, hepatitis C virus research, and disrupting RNA interference pathways.