Reviews & Analysis

Developing therapeutic agents that target the peptidylarginine deiminase PAD4 requires better understanding of the function of the enzyme. Isozyme-selective antibodies that alter PAD4 activity have been identified recently, revealing unique modes of action.

A second-timescale optogenetic strategy DeKinomics was developed, enabling the study of downstream events of kinases in a gain-of-function manner. Using this technique, UBA1, an E1 enzyme that initiates the ubiquitination cascade, was found to be directly regulated by tyrosine phosphorylation.

The K⁺ ion channel KCNQ2 modulates neuronal excitability and is targeted by retigabine, an anti-epileptic drug that enhances the probability of channel opening. New activators have now been discovered to increase unitary conductance through an unprecedented mechanism.

The rules for designing cyclic peptides with drug-like properties are unclear. Two studies now show how cyclic peptide libraries can be created to optimize properties such as cell permeability before screening for binding activity. The approach has led to a macrocyclic peptide inhibitor for KRAS that has reached clinical trials.

Sirtuins remove post-translationally added acyl groups from protein lysines. New work shows the surprising metabolic fate of acyl groups removed from mitochondrial proteins—they react nonenzymatically with essential polyamine spermidine, forming previously unknown monoacylated N-glutarylspermidines and diacylated N-glutaryl,N-acetylspermidines.

Screening of a chemical library identifies a novel ferroptosis inhibitor that directly interferes with the formation of intracellular membrane contacts between the endoplasmic reticulum (ER) and mitochondria (ERMCS), commonly referred to as mitochondria-associated membranes (MAMs).

Nature has evolved elegant enzymatic strategies to cyclize peptides, resulting in complex macrocyclic compounds with potent biological activities. A study illustrates the diverse chemical versatility of one such remarkable enzyme family, the cytochrome P450 macrocyclases, which form new biaryl crosslinks in ribosomal peptidic natural products.

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.

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.

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.

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.