This Perspective discusses how macromolecular condensation can regulate the electrochemistry to affect biological function in living cells and provides a framework to study the electrochemical functions of biomolecular condensates.

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.

Research in the early days of chemical biology was mostly limited to the application of chemical tools to model cell lines grown in incubators. Now, discoveries are being made in more physiologically relevant systems, from tissues to organisms, using precisely targeted molecules. The 2023 Chemical Biology & Physiology meeting (in Portland, Oregon) discussed the latest advances in the field, with research from around the globe demonstrating that the transition to making discoveries at the chemical biology–physiology interface is happening now.

The integration of a new orthogonal redox cofactor opens opportunities for controlling reaction equilibria. Because it does not interfere with cellular redox homeostasis, this approach enables the precise tuning of metabolic pathways and the optimization of microbial bioproduction, independently of canonical redox balancing.

A nanopore-based framework distinguishes and quantifies tyrosine sulfation from phosphorylation in peptide mixtures and native protein fragments and determines the sequence of the sulfated fragment.

An automation tool has been designed that enables partitioning of an algorithm into subcircuits split across cells for biological computing. The tool was applied to a hashing algorithm requiring 110 logic gates across 66 cells.

The use of an adenine base editor enables identification of functional serine, threonine and tyrosine residues that impact cell fitness on a genome-wide scale with possible involvement in phosphorylation, structural maintenance and cancer biology.

A tRNA modification, named 2-aminovaleramididine (ava²C), has been discovered in plant organelles and bacteria. Structural analysis shows specific codon recognition by this modification, highlighting the evolutionary diversity of the essential tRNA modifications.

Li, Cheng, Yu and colleagues have discovered a Cas13j family, including the compact and highly efficient LepCas13j (529 aa) and ChiCas13j (424 aa), with promising applications in RNA editing in vivo.

Development of a paralog-hopping approach leveraging chemical proteomic data on covalently liganded cysteines revealed an allosteric pocket shared by cysteine-containing and cysteine-less paralogous cyclin E proteins.

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.