Cell Chemical Biology

Intracellular cyclization-coupled peptide library screening yields potent transcription factor antagonists Brennan et al. integrate chemical peptide cyclization with live-cell screening, expanding the functional chemical space accessible to intracellular genetically encoded peptide libraries. The approach delivers functional cyclic peptide inhibitors of the oncogenic transcription factor CREB1, illustrating a general strategy for targeting transcription factor-DNA interactions previously considered “undruggable.”

Online now! Online now! Intracellular cyclization-coupled peptide library screening yields potent transcription factor antagonists #chembiol

Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells Pang et al. identify a unique CD8+ T cell state (Tpeec) induced by NQO1-mediated redox cycling. They demonstrate that lawsone treatment redirects glucose flux into the pentose phosphate pathway, simultaneously enhancing T cell stemness and mitochondrial fitness. This metabolic rewiring improves the efficacy of adoptive T cell therapy against solid tumors.

Online now! Online now! Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells #chembiol

Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS van Tienen et al. develop CysMAP, a systematic cysteine scanning and covalent screening platform that maps druggable protein pockets. Applied to KRAS(G12D), CysMAP uncovers a novel pocket between switch-II and α3 whose covalent engagement stabilizes a distinct KRAS conformation, expanding strategies for targeting oncogenic RAS.

Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS

Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1 RNA-binding proteins are central to the function of a cell and tightly associated to genetic diseases. Florio et al. report the molecular basis of NONO targeting by (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity, highlighting the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO.

Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1

Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO Lindsey et al. integrate structural studies with activity-based protein profiling to characterize a druggable pocket proximal to the RNA-binding interface of NONO that can be covalently targeted by low-reactivity chlorofluoroacetamide ligands to remodel the transcriptomes and suppress the growth of cancer cells.

Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO

Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS van Tienen et al. develop CysMAP, a systematic cysteine scanning and covalent screening platform that maps druggable protein pockets. Applied to KRAS(G12D), CysMAP uncovers a novel pocket between switch-II and α3 whose covalent engagement stabilizes a distinct KRAS conformation, expanding strategies for targeting oncogenic RAS.

Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS

Exporter Mdr1 as an importer is an achilles’ heel for combating drug-resistant Candida Chen et al. reveal that the fungal multidrug exporter Mdr1 can function as an importer for cyanine derivatives such as MKT-077, turning a key resistance mechanism into a therapeutic vulnerability and offering a new strategy to combat antifungal resistance.

Exporter Mdr1 as an importer is an achilles’ heel for combating drug-resistant Candida

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation Liu et al. reveal that lactate, an aerobic glycolysis product, promotes NLRP3 inflammasome activation and pyroptosis. NLRP3 is identified as a target of lactylation, and K24 and K565 have potential to facilitate inflammasome activation. In vivo, lactate inhibition attenuates inflammatory responses in polymicrobial sepsis model.

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis Kim and Hergott et al. uncover a metabolic foundation for the pathogenic inflammation arising from TET2-mutant clonal hematopoiesis (CH). In myeloid cells, TET2 loss disinhibits the nutrient sensor/glycosyltransferase OGT, driving aberrant and inflammatory lipid accumulation via the metabolic enzyme ACLY. Inhibiting ACLY offers a therapeutic strategy for controlling CH-related hyperinflammation.

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis

The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation Regulating macrophage-mediated inflammation is critical for treating inflammatory disorders. Zhang et al. find MROH7 inhibits IL-1β via Arachidonic acid-dependent LBP acetylation/degradation, suppressing NF-κB signaling, highlighting MROH7 as a therapeutic target.

The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation

Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities Ke et al. review emerging proximity-inducing modalities—phosphorylation-targeting chimera, including PhosTACs, DEPTACs, PhoRCs, and PHICS—that modulate protein phosphorylation via an “event-driven” mechanism. They highlight how these bifunctional approaches offer a different avenue for phosphorylation-targeted therapeutics development, discussing recent applications and challenges in this field.

Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities

Decoding E1-E2 specificity: How UBA6 prioritizes BIRC6 for ubiquitin conjugation Ubiquitin-conjugating enzyme BIRC6 displays high specificity toward ubiquitin-activating enzyme UBA6. In a study recently published by Nature Structural & Molecular Biology, Riechmann et al. unveiled the mechanism underlying UBA6-BIRC6 specificity and its mediated thioester switch, which broadened the understanding of the E1-orchestrated E2 hierarchy.

Decoding E1-E2 specificity: How UBA6 prioritizes BIRC6 for ubiquitin conjugation

Beyond a degrader: VHL reprograms hypoxic metabolism The von Hippel-Lindau (VHL) protein is known for degrading hydroxylated proteins in normoxia, but its role under hypoxia remains unclear. In a recent report in Cell Metabolism Li et al. demonstrate that mitochondrial VHL remodels amino acid metabolism under chronic hypoxia to support cell growth, independent of hydroxylated protein degradation.

Beyond a degrader: VHL reprograms hypoxic metabolism

Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts Liang et al. quantified and profiled natural peptidoglycan fragments (PGNs) released by a panel of bacterial species. They found that prolonged exposure to Lactobacillaceae-derived PGNs induced tolerance in murine macrophages to subsequent TLR stimulation. They demonstrated that the intraperitoneal administration of the natural PGN GM-AQK protected mice against DSS-induced colitis.

Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts

What’s the good word? Lactobacilli produce peptidoglycan fragments with the right structure to induce tolerance during colitis Pattern recognition receptors detect peptidoglycan and trigger inflammatory responses promoting bacterial clearance. So, how do our gut bacteria survive? In this issue of Cell Chemical Biology, Liang et al. determine the structures of peptidoglycan fragments released by beneficial bacteria that mediate a NOD2-dependent reduction in inflammatory responses to bacterial products.

What’s the good word? Lactobacilli produce peptidoglycan fragments with the right structure to induce tolerance during colitis

Cover image for Cell Chemical Biology employing the “Hou Yi shooting the suns” motif

New issue alert! The February edition of Cell Chemical Biology is here with must-read studies and a review. Which article will you read first? Tell us after you check it out: http://dlvr.it/TR3DfM #ChemicalBiology

Lysosome-targeting chimeras enable targeted protein degradation Bozhao Li et al. review lysosome-targeting chimeras (LYTACs) as a transformative strategy for degrading extracellular and membrane proteins. They outline receptor-guided design principles, endocytic routing mechanisms, and translational challenges, highlighting how LYTACs expand targeted protein degradation beyond the proteasome.

Online now! Online now! Lysosome-targeting chimeras enable targeted protein degradation #chembiol

Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS van Tienen et al. develop CysMAP, a systematic cysteine scanning and covalent screening platform that maps druggable protein pockets. Applied to KRAS(G12D), CysMAP uncovers a novel pocket between switch-II and α3 whose covalent engagement stabilizes a distinct KRAS conformation, expanding strategies for targeting oncogenic RAS.

Online now! Online now! Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS #chembiol

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis Kim and Hergott et al. uncover a metabolic foundation for the pathogenic inflammation arising from TET2-mutant clonal hematopoiesis (CH). In myeloid cells, TET2 loss disinhibits the nutrient sensor/glycosyltransferase OGT, driving aberrant and inflammatory lipid accumulation via the metabolic enzyme ACLY. Inhibiting ACLY offers a therapeutic strategy for controlling CH-related hyperinflammation.

Online now! Online now! Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis #chembiol

Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts Liang et al. quantified and profiled natural peptidoglycan fragments (PGNs) released by a panel of bacterial species. They found that prolonged exposure to Lactobacillaceae-derived PGNs induced tolerance in murine macrophages to subsequent TLR stimulation. They demonstrated that the intraperitoneal administration of the natural PGN GM-AQK protected mice against DSS-induced colitis.

Online now! Online now! Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts #chembiol

Mechanosensation promotes broad-spectrum antiviral defense through membrane remodeling Huang et al. define the mechano-antiviral response system (MARS) and reveal that mechanical force triggers Piezo1-dependent membrane stiffening. This establishes a broad-spectrum, interferon-independent antiviral defense that can be exploited by small-molecule agonists or vibration.

Online now! Online now! Mechanosensation promotes broad-spectrum antiviral defense through membrane remodeling #chembiol

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation Liu et al. reveal that lactate, an aerobic glycolysis product, promotes NLRP3 inflammasome activation and pyroptosis. NLRP3 is identified as a target of lactylation, and K24 and K565 have potential to facilitate inflammasome activation. In vivo, lactate inhibition attenuates inflammatory responses in polymicrobial sepsis model.

Online now! Online now! Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation #chembiol

The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation Regulating macrophage-mediated inflammation is critical for treating inflammatory disorders. Zhang et al. find MROH7 inhibits IL-1β via Arachidonic acid-dependent LBP acetylation/degradation, suppressing NF-κB signaling, highlighting MROH7 as a therapeutic target.

Online now! Online now! The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation #chembiol

Advances in degradomics technologies to assess proteolytic cleavage events Ziegler et al. outline how modern proteomics and mass spectrometry enable precise identification of protease-generated cleavage sites. They highlight enrichment-based and enrichment-free degradomics workflows used to map N- and C-terminal peptides, define protease specificity, and uncover substrate networks that drive health and disease.

Online now! Online now! Advances in degradomics technologies to assess proteolytic cleavage events #chembiol

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Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO Lindsey et al. integrate structural studies with activity-based protein profiling to characterize a druggable pocket proximal to the RNA-binding interface of NONO that can be covalently targeted by low-reactivity chlorofluoroacetamide ligands to remodel the transcriptomes and suppress the growth of cancer cells.

Online now! Online now! Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO #chembiol

Targeted discovery of aromatic glycosides with dual detoxification effects via a highly customized molecular networking platform

An interactive resource mapping the proteome and reactive cysteine landscape across the NCI-60 reveals cell and tissue-specific profiles

Mechanistic diversity of Bacteroides fragilis toxins and neutralization with single domain antibody Guo et al. demonstrate structural and mechanistic diversity among three BFT subtypes, highlighting BFT-2’s heightened potency, providing evidence that the BFTs cleave E-cadherin EC4 domain. They further identify the single-domain antibody that effectively blocks BFT activity in vitro and mitigates the pathogenicity of enterotoxigenic B. fragilis in a colitis mouse model.

Mechanistic diversity of Bacteroides fragilis toxins and neutralization with single domain antibody

Identification of aryl hydrocarbon receptor as a functional target that enhances astrocytic ApoE secretion