Reviews & Analysis

Transporters and channels have strong potential as drug targets, but drug discovery targeting these membrane-embedded molecules is challenging. Fragment-based ligand discovery combined with chemical proteomics offers a promising solution to the search for inhibitors of solute transporter family members.

Macromolecules can undergo liquid–liquid phase separation to form condensates that have critical roles in biological functions and dysfunctions. A new study demonstrates that differences in micropolarity between components is a prime determinant of the multiphasic architecture of biomolecular condensates.

Half a century after its discovery, platelet-activating factor (PAF) is now recognized as a ferroptosis-activating phospholipid that contributes to tubule cell damage and nephron loss in acute kidney injury.

Antigen reorientation via oligoD, a label-free, alum-based technique, guides immunofocused, broadly reactive antibody responses.

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.