This Perspective discusses the application of algorithmic methods throughout the preclinical phases of drug discovery to accelerate initial hit discovery, mechanism-of-action elucidation and chemical property optimization.

In May 2024, ‘Protein Degradation in Focus’, a special symposium aimed at bringing together scientists in the targeted protein degradation (TPD) field, was held in Dundee, UK. David Zollman and Kirsten McAulay report on the topics discussed and the exciting outlook for science in the TPD space.

Orally bioavailable, high molecular weight macrocyclic peptides that inhibit difficult-to-drug protein–protein interactions are of high therapeutic value, and rules for their design were proposed recently. Here, we emphasize the danger of rules that provide a false impression of the lipophilicity required of a clinical candidate.

Cryo-electron microscopy structures of paenilamicin-stalled ribosomes showed that it has a unique ribosome-binding site located between the A- and P-site tRNAs. Additional biochemical assays demonstrated that paenilamicins inhibit protein synthesis by blocking the movement of mRNA and tRNA through the ribosome during the elongation phase.

The MBD2c splicing variant of MBD2 that is essential for nuclear transcription translocates to the mitochondria to regulate mitochondrial DNA transcription and respiration and is linked to drug resistance in cancer cells.

Wendrich, Gallant and colleagues find that USP53 and USP54 are active deubiquitinases, with USP53 removing ubiquitin chains from substrate proteins in a chain-linkage-directed manner, and provide biochemical and structural insights into their mechanism, cellular substrates and disease implications.

An optogenetic tool called Opto-OGT has been developed that enables researchers to probe pathways involving modifications with O-linked β-N-acetylglucosamine (O-GlcNAc) such as OGT, mTOR and AMPK signaling with high spatiotemporal precision. The method is based on fusing a photosensitive cryptochrome protein to an O-GlcNAc transferase and enables OGT to be reversibly activated with blue light.

Loveless, Carlson and colleagues describe peCHYRON, a DNA recorder that propagates an unending chain of insertions. Each link contains a randomizable 3-bp ‘signature’ sequence that serves to record a cellular event in the order it occurred.

The sodium salts in corn stover hydrolysates have been identified as important inhibitors for cellulosic ethanol production. Adaptive evolution generated a robust yeast that converted both glucose and xylose into biofuel. Subsequent reverse engineering created a genetically defined yeast with equivalent performance to the evolved strain.

A high-throughput precision oncology pipeline for pharmacotranscriptomic profiling using live-cell barcoding and single-cell RNA sequencing was developed. Using this approach revealed a drug resistance feedback loop in high-grade serous ovarian cancer, suggesting that combining phosphatidylinositol 3-OH kinase, protein kinase B and mammalian target of rapamycin inhibitors with epithelial growth factor receptor inhibitors may overcome resistance.