Articles

Hanswillemenke, Hofacker and colleagues developed a proximity labeling-based method to identify protein interactome of small molecules and RNA drugs within living cells, facilitating the design and development of RNA drugs with enhanced pharmacological properties.

A new design for vaccines consisting of reorienting the viral glycoprotein in an ‘upside-down’ configuration broadens immune responses to diverse influenza subtypes and serves as a proof of concept for designing a universal flu vaccine.

A small molecule, CGI1746, was identified to block ferroptosis acting through the sigma-1 receptor, a chaperone primarily at endoplasmic reticulum–mitochondria contacts to mediate calcium transfer.

Qin et al. find that cell detachment induces condensation of LATS2, a core kinase of the Hippo pathway. These LATS2 condensates protect LATS2 from degradation by the ubiquitin–proteasome system, thereby promoting the assembly of Hippo signalosomes for pathway activation.

Integrated chemoproteomic development of selective small-molecule SLC15A4 inhibitors and their functional characterization establish SLC15A4 as a druggable target for autoimmune conditions.

Hernandez-Candia et al. introduce BTBolig, a chemical-based tool to manipulate biomolecular condensates, and CoSMo, a method for control of condensate maturation. When used together, the authors observe dynamic interactions of condensates with protein chaperones.

The small molecule SRI-41315 induces the degradation of the translation termination factor eRF1 to enhance stop codon readthrough. Coelho, Yip et al. reveal that SRI-41315 is a metal-dependent molecular glue that traps eRF1 on terminating ribosomes.

Identification of a small molecule (Ebio1) reveals a unique activation mechanism for the KCNQ2 potassium channel. Ebio1 induces a twist-to-open movement in the S6 helices, creating an extended channel gate with enhanced conductance.

Weng et al. developed a photocaged lysine-based gain-of-function strategy termed DeKinomics to systematically dissect kinase activity with high specificity and temporal resolution under living conditions.

Using single-molecule and biochemical methods, Göse et al. demonstrated that the helicase-like ATPase of a Type III restriction enzyme establishes DNA sliding through a sequential series of nucleoprotein remodeling steps driven by DNA translocation.

Untargeted comparative metabolomics revealed N-acylspermidines as conserved metabolites downstream of mitochondrial sirtuins that provide direct evidence for their in vivo deacylation functions and may contribute to sirtuin-dependent phenotypes.

A chemoproteomic workflow was developed to determine the interaction sites of photoaffinity probes in cells, enabling the identification of diverse binding pockets and providing evidence of their tractability to small-molecule action.

Peptide epimerization is a common but enigmatic post-translational modification found in antibiotics formed from ribosomally synthesized and post-translationally modified peptides. Now, crystallographic snapshots, spectroscopy and biochemical investigations have provided insight into the mechanism of peptide epimerization catalyzed by radical S-adenosyl-l-methionine epimerases.

Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of small cyclic peptides while enabling the simultaneous interrogation of activity and permeability. This approach was applied to the disease target thrombin to discover peptides with high affinity, stability and oral bioavailability of up to 18% in rats.

Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.

Qi et al. used phage-assisted evolution to optimize SlugCas9, a compact Cas9 nuclease, for NNG PAM recognition and developed a SlugCas9-NNG based adenine base editor for single AAV delivery.

A workflow integrating tools from bioinformatics, structural biology and synthetic biology has been developed that enables the rapid design of pili-enabled living materials. This approach allows mining of pili-producing nonpathogenic chassis, understanding of the pili structure and assembly, and engineering of pili-enabled living materials in a systematic and sequential manner.

Efforts to rationally engineer nonribosomal peptide synthetase (NRPS) enzymes have focused on making individual modifications. Here the authors describe a targeted random engineering approach that uses thousands of NRPS domains amplified from the soil metagenome for mass substitution experiments.

Oxygen sensitivity hampers applications of metal-dependent CO₂ reductases. Here, Oliveira et al. describe how an allosteric disulfide bond controls the activity of a CO₂ reductase, preventing its physiological reduction during transient O₂ exposure and allowing aerobic handling of the enzyme.

Cui et al. developed LAUNCHER, a single-component switch using potyviral protease, which offers a high signal-to-noise ratio for precise payload release, enabling versatile cellular applications and enhanced synthetic circuit performance.