Staphylococcus aureus is a leading cause of bacteria-associated mortality worldwide. New tools are needed to both image and treat this pathogen. We previously identified a group of S. aureus serine hy...

We report a ‘direct-to-biology’ (D2B) approach for optimising covalent acrylamide binders of protein targets and apply this to the identification of a selective and cell-active inhibitor of Werner (WR...

Peptide macrocycles are promising therapeutics for a variety of disease indications due to their overall metabolic stability and potential to make highly selective binding interactions with targets. R...

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development and important tools for target validation. When appropriately opti...

Automated glycan assembly (AGA) streamlines the synthesis of complex oligosaccharides. The reducing end of the oligosaccharide serves as an attachment site to the polymer support to liberate a free reducing end or an aminopentanol for ready conjugation to carrier proteins or surfaces. The facile installation of different aglycons on oligosaccharides has not been possible via AGA until now. Here, we describe a latent-active approach enabled by a traceless photolabile linker that allows for bidirectional AGA and ready introduction of various aglycons. Oligosaccharide thioglycosides, peptidoglycans, prototypical saponins, and click-chemistry-based conjugates are synthesized to illustrate the versatility of the method.

Liu et al. report that DNMT1 inhibition causes transient accumulation of hemi-methylated DNA at CpG islands, which stimulates UHRF1-mediated H3K18ub. This enhances SUV39H1/H2 activity, nucleates new H...

Parker et al. demonstrate that some proteins responsible for organizing ribonucleoprotein granules can chaperone intermolecular RNA-RNA interactions in addition to their role in scaffolding. These findings cement RNA-RNA interaction networks as a key component of granules, highlighting the need to further explore the regulation of RNA dynamics within granules.

Small molecules promoting protein–protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN–DDB1 and WEE1 provides a model of the protein–protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

A cysteine-reactive degrader of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nonstructural protein 14 (nsp14) was identified, which mediates degradation through electrophile-induced gl...

Photoaffinity labeling (PAL) methodologies have proven to be instrumental for the unbiased deconvolution of protein–ligand binding events in physiologically relevant systems. However, like other chemi...

The bacterial sequence data publicly available at the global DNA archives is a vast source of information on the evolution of bacteria and their mobile elements. However, most of it is either unassemb...