Reviews & Analysis

Understanding the role of pyrophosphorylation requires specific analytical strategies to discriminate it from protein phosphorylation. A custom workflow reveals that nucleolar protein pyrophosphorylation in human cells regulates the transcription of ribosomal DNA.

Ribosomally synthesized and post-translationally modified peptide (RiPP) natural products typically rely on substrate recognition through remote protein–protein interaction sites. Now, an atypical dehydratase, whose activity is directed by neighboring azole modifications, has been shown to produce a highly modified peptide hybrid bearing dehydroamino acids, enabling the synthesis of members of the dehydrazole family of RiPPs.

Reprogramming intercellular mechanotransduction and signaling pathways is still challenging. A recent advance uses a plug-and-play DNA nanodevice to allow non-mechanosensitive receptor tyrosine kinase (RTK) to transmit force-induced cellular signals.

Chemical approaches, such as those that leverage induced proximity, targeted degradation, synthetic gene regulators or protein design offer opportunities to therapeutically target cellular processes that have long been thought of as undruggable. We report on the progress and the potential for transformative collaborations between fields discussed at the 2023 Bringing Chemistry to Medicine symposium at St. Jude Children’s Research Hospital.

Peptide vaccines use antigenic peptide fragments to induce an immune response but are problematic because of the short half-life of peptides. A study now reports thioamide substitution in the peptide backbone as a strategy to enhance resistance to proteolysis and promote binding to the MHC I complex for T cell activation.

Detection of intracellular lipolysaccharide (LPS) activates an immune response initiated by the non-canonical inflammasome. ATGL has now been identified as a negative regulator of this pathway that dampens inflammation by removing LPS’ acyl chains, preventing the activation of inflammatory caspases and cytokines.

Chemogenetic profiling can reveal genetic determinants that coordinate phenotypic responses to therapeutics, along with predicting potential pathways of resistance. A new analytical method for evaluating chemogenetic profiles reveals contributions from death-regulatory genes.

BURP-domain proteins belong to an emerging class of autocatalytic copper-containing proteins that modify themselves after synthesis. Now, a report explains how their structure and metal coordination sphere control the installation of crosslinks within the core peptide, and shows how nature leverages mechanistic paradigms to create diversity.

An integrative approach has now enabled elucidation of the complete biosynthetic pathway of a prominent saponin adjuvant. Reconstruction of the whole biosynthetic pathway in a heterologous host provides new perspectives for the biotechnological supply of this immunostimulant.

Reprogramming of the genetic code allows the synthesis of proteins using new building blocks, thus opening the door to the development of a wider variety of medicines and biocatalysts; however, it is currently limited to α-amino acids. A new study has now reported the incorporation of β-linked and α,α-disubstituted monomers into a ribosome-synthesized protein.

The rate of ATP production and the total mass of enzymes were quantified for both glycolysis and mitochondrial respiration to determine the proteome efficiency of these pathways. Per unit of enzyme mass, mitochondrial respiration generates energy faster than glycolysis and is thus more proteome efficient. Despite being less proteome efficient, constitutive glycolysis comes with the benefit of rendering cells robust to hypoxia.

Kir4.1 potassium channels expressed in astroglial cells critically regulate extracellular potassium concentration in the brain. A new study reports that blocking the flow of potassium ions into astrocytes by inhibiting Kir4.1 induces rapid-onset antidepressive effects in rodents.

Labeling of endogenous proteins with chemical probes is highly desirable for life science studies. The combination of RNA base editing and site-specific incorporation of non-canonical amino acids allows the introduction of small chemical tags into endogenous proteins in living cells.

Inhibitors of KRAS G12C have shown that directly targeting RAS is possible, but G12C is only one of many RAS driver mutations. Covalent targeting of another major variant, G12D, raises hope for treating other groups of patients with KRAS-mutant tumors.

Chemically reactive metabolites such as formaldehyde are often toxic and are proposed to react promiscuously with biomolecules. New work shows that some reactive sites on proteins are uniquely sensitive to formaldehyde, leading to functionally important regulation of protein and cell functions.

This Review provides an overview of different RNA base editing technologies, including the RNA-targeting platforms and modification effectors, with a focus on the emerging programmable RNA base editors and their potential in correcting pathological mutations.

Developing inhibitors for SH2 domains is challenging due to their shallow pockets and highly charged ligands. Structure-guided drug design has enabled the discovery of a cell-permeable covalent inhibitor of the SOCS2 SH2 domain, a key regulator of cytokine signaling pathways.

O-linked N-acetylglucosamine (O-GlcNAc) is an endogenous form of glycosylation that alters the structure of α-synuclein amyloid fibrils and attenuates their pathogenetic properties. The modified fibrils have a significantly reduced ability to seed the aggregation of endogenous α-synuclein in cultured neurons and in mice brains in vivo, which results in reduced pathology.

Nonribosomal peptide synthetases produce diverse natural products, including many valuable therapeutics. Although the condensation domains that catalyze peptide bond formation in these multifunctional enzymes have been difficult to engineer, a yeast display system that was developed to screen millions of variants now enables efficient reprogramming of synthetase substrate specificity.

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.