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The mechanisms of stalled fork degradation in BRCA1/2-deficient cells remain unclear. UFL1, an UFM1-specific E3 ligase, was found to catalyze PTIP UFMylation at lysine 148, promoting stalled fork degradation by the MRE11 nuclease.

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.

Developing disease-modifying drugs for neurodegenerative diseases has been very challenging. Now a machine learning approach has been used to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies. Compounds that bind to the catalytic sites on the surface of the aggregates were identified and then progressively optimized into secondary nucleation inhibitors.

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.

Through rational engineering of A3A deaminase, Yang and colleagues have designed CBEs termed haA3A-CBEs, which feature a condensed editing window and minimal off-target effects that are independent of defined sequence contexts and methylation status.

TERT was dephosphorylated by the protein phosphatase activity of the gluconeogenic enzyme FBP1, leading to inhibition of TERT nuclear translocation and telomere function. Lipid nanoparticle-delivered FBP1 mRNA blunts tumor growth in mice.

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.

A proteomics and computational approach was developed to map the proximal proteome of the activated μ-opioid receptor and to extract subcellular location, trafficking and functional partners of G-protein-coupled receptor activity.

Exportin-1 (XPO1) was identified as the target of small molecules suppressing T cell activation. Selective disruption of the chromatin scaffolding function of XPO1 without blocking nuclear export implicates XPO1 as a target in autoimmunity.

Wenzell et al. developed a massively parallel screening platform to interrogate the sensitivity of signal peptides (SPs) to Sec61 inhibitors. The platform revealed how distinct inhibitors achieve sequence-dependent SP discrimination.

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.