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Communications Chemistry is pleased to introduce a Collection of research works focused on recent developments within the interdisciplinary field of Covalent chemical probes. Here, the Guest Editors h...

Cross-linking mass spectrometry faces challenges due to low reaction efficiencies and complex matrices in protein–protein interaction (PPI) studies. Here, the authors enhance an Azide-A-DSBSO-based in...

KRAS mutations, particularly KRAS(G12D), are prevalent in various cancers, yet effective treatments remain elusive. Here, the authors introduce ASP3082, a pioneering KRAS(G12D)-selective degrader, dem...

Grafted Coiled Coils

Self-assembled peptides are promising templates for the design of inhibitors of protein–protein interactions (PPIs) because they can be endowed with affinity- and selectivity-defining amino acids alon...

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Covalent Peptide Library Screening Platform A peptide library screening platform was developed to discover covalent transcription factor inhibitors. It identified an antagonist cysteine residue which...

Although using DNA-encoded libraries (DELs) to find small molecule binders of target proteins is well-established, identifying molecules with functions beyond binding remains challenging in pooled scr...

Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Here, the authors report photoaffinity probes based on the imidazopyrazine scaffold, whic...

Self-assembled peptides are promising templates for the design of inhibitors of protein-protein interaction (PPI) because they can be endowed with affinity- and selectivity-defining amino ac-ids alongside favorable physicochemical properties such as solubility and stability. Here we describe a tunable coiled-coil scaffold and its interaction with MCL-1, an α helix-binding anti-apoptotic protein and important target in oncology. We explore the role of oligomerization, multivalency and co-operativity in PPI inhibition. Hot-spot residues from an MCL-1 binding peptide (NOXA B) are grafted onto the outer surfaces of homo- and hetero-dimeric coiled-coil peptides to obtain inhibitors with mid-nM potency and selectivity over BCL-xL. Binding of ho-modimeric coiled coils to MCL-1 is positively co-operative resulting in stabilization of both part-ners. Homodimeric coiled coils support binding of two copies of the target protein. Modification of the coiled-coil sequence to favor assembly of higher-order scaffolds (trimer and tetramer), negatively impacts inhibitory potency, with AlphaFold2 modelling and biophysical data indicat-ing a complex interplay between coiled-coil oligomerization and target binding. Together, these data establish dimeric coiled coils as the most-promising of such scaffolds to develop inhibitors of α helix-mediated PPIs.