Reviews & Analysis

Cyclic peptides can bind challenging disease targets, but their oral application is hindered by digestion and absorption issues. We developed a versatile method for the synthesis and functional screening of vast numbers of synthetic cyclic peptides and identified peptides with high inhibitory activity, stability and oral bioavailability in rats.

The requirement for a protospacer adjacent motif (PAM) is a well-known limitation of the CRISPR–Cas9 system, as it restricts the range of sequences that can be targeted. To address this limitation, we demonstrate a phage-assisted evolution approach for engineering a compact SlugCas9, simplifying its PAM requirement and broadening its DNA targeting scope.

Cyclic tetrapeptides (CTPs) have great potential for materials and therapeutics; however, synthesizing these molecules remains a significant challenge. Now, an enzyme has been developed that enables efficient N-to-C cyclization of linear tetrapeptidyl substrates to form structurally diverse CTPs.

Analyzing glycans is challenging because of their structural diversity and complexity and the lack of analytical techniques capable of resolving pools of similar glycan structures. A new method now enables imaging of single glycans, providing direct observation of individual glycans and glycoconjugates.

Small molecules and drugs are not homogenously distributed across cells, and are instead enriched in distinct subcellular compartments and membraneless biomolecular condensates. A new study lays out the path to identifying chemical features or ‘rationales’ that confer condensate-selective partitioning of small molecules.

Cells contain compartments composed of phase-separated protein condensates. We find that these condensates have a unique chemical microenvironment that enriches amphipathic metabolites such as phospholipids. Therefore, condensates are mixtures of proteins, nucleic acids and specific metabolites. The presence of phospholipids and other amphipathic metabolites might enable condensates to facilitate specific metabolic reactions.

Controlled interactions between macromolecules are fundamental regulatory layers. Hijacking these circuits via proximity-inducing small molecules offers many therapeutic opportunities. The organizers, Georg Winter and Cristina Mayor-Ruiz, report on the latest trends in this emerging field discussed at the 39th IRB-BioMed Conference in Barcelona.

Terpenoids bearing carbon skeletons derived from nonisoprene units are rare and considered noncanonical. Now, a genome-mining study has uncovered previously unknown noncanonical C₁₆ terpenes and their biosynthetic pathways from bacteria. The findings suggest that noncanonical terpenoids are diverse and widespread in nature.

The integrated stress response affects cell survival or death under stress conditions, and depends on the activity of the eukaryotic translation initiation factor eIF2B. New research identifies a protein helix that modulates this response by controlling the structural states of eIF2B.

LIS1 is an essential cofactor for the assembly of the cytoplasmic dynein transport machinery. How LIS1 binding affects dynein motility was unclear. Single-molecule experiments reveal that Pac1 (the yeast homolog of LIS1) binding reduces dynein speed by slowing its detachment from microtubules and does not disrupt the mechanism by which it generates force.

DNA-encoded libraries are a powerful tool to identify novel chemical inducers of proximity such as targeted protein degraders, even without a known binder for the target protein.

Defining subcellular locations and interacting partners for proteins accelerates their functional characterization. A new in vivo tagging approach achieves both for mitochondrial matrix proteins and helps connect a key oxidoreductase to coenzyme Q biosynthesis.

Genetically encoded tools to manipulate redox metabolism are in high demand for investigating the underlying mechanism of cofactor imbalances in mammalian systems. A new tool enables the induction and interrogation of NADH reductive stress.

Traditional production of therapeutic secretory proteins often experiences delays between protein synthesis and therapeutic effects. An inducible protease-dependent protein secretion technique allows the immediate secretion of pre-translated biotherapeutic agents after exposure to chemical cues, tumor-specific antigens or photons.

We developed a versatile lipid probe — MAO–SiR — to visualize the structure and dynamics of the inner mitochondrial membrane (IMM). MAO–SiR assembles in situ from two cell-permeant small molecules to image the IMM selectively, continuously and at super resolution for extended periods of time without extensive photobleaching or toxicity.

The quality of chemical tools and their appropriate use determine the quality and reliability of scientific data based on their use. Now, two papers extend criteria to new modalities and critically review adherence to established guidelines.

Activation of STING-dependent signal transduction results in adaptive immune responses that promote antitumor immunity. A recent study has identified a small-molecule STING agonist that functions by binding to a newly discovered ligandable site to induce high-order STING oligomerization.

Computational approaches are emerging as powerful tools for the discovery of antibiotics. A study now uses machine learning to discover abaucin, a potent antibiotic that targets the bacterial pathogen Acinetobacter baumannii.

Protein lipidation is an important post-translational modification that can be difficult to study. New amino acids with side chains that mimic naturally occurring lipid modifications stand to facilitate the study of lipidated proteins.