Natural coumarins represent a diverse group of secondary metabolites with a wide range of biological activities. However, their specific molecular targets have remained largely unexplored. Employing chemical proteomics, a comprehensive analysis of the protein targets of the natural coumarin fraxetin has been

Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12F36V-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.

Nature - A new class of molecules can recruit downstream transcription factors or endogenous cancer drivers to cell death promoters and activate the expression of these genes.

Nature Chemistry - Profiling subcellular multi-omics with spatiotemporal resolution remains a key challenge in cell biology. Now an orthogonal photocatalytic labelling strategy has been developed...

Nature Chemical Biology - A chemoproteomic approach is developed that examines changes in ligand binding-induced accessibility by globally labeling reactive proteinaceous lysines, revealing the...

Over the past decade, numerous metabolomics techniques have been developed using liquid chromatography–mass spectrometry (LC-MS). These methodologies have yielded significant findings and facilitated ...

Structurally diverse natural products are a promising source of antibiotics. Here, the authors report the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related...

A naturally occurring stand-alone and intermolecular Diels–Alderase, MaDA, has been identified from Morus alba cell cultures. MaDA is a FAD-dependent enzyme, which catalyses the intermolecular [4+2] c...

Peptide sequencing is critical to the advancement of proteomics research. Here, the authors present π-PrimeNovo, a non-autoregressive deep learning model that achieves high accuracy and up to 89x fast...

The fraction of sp3-hybridized carbons (Fsp3) and the fraction of stereogenic carbons (FCstereo) are two widely employed scores of molecular complexity with strong links to biologically relevant features. However, they do not comprehensively express molecular topology, and they often do not match the chemical intuition of complexity. We propose the spacial score (SPS) as an empirical scoring system that builds upon the principle underlying Fsp3 and FCstereo and expresses the spacial complexity of a compound in a uniform manner on a highly granular scale. The size-normalized SPS (nSPS) can differentiate distributions of natural products and synthetic compounds and is applicable in the analysis of biological activity data. Analysis of the ChEMBL database revealed general trends of increasing selectivity and potency with increasing nSPS. SPS can also be used advantageously in planning and analysis of synthesis programs for direct comparison of chemical transformations and intermediates in reaction sequences.

Mass-spectrometry-based phosphoproteomics enables the analysis of thousands of protein phosphorylation events across the human proteome. However, there is a lack of scalable, hypothesis-free, and stat...

A visible-light-controlled lysine-selective crosslinking (VL-XL) strategy is introduced for exploring protein complexes and dynamic interactomes in live cells. By synergistically integrating the adva...

Extracellular and membrane-associated proteins play essential roles in nearly all our body’s biochemical processes and are implicated in cancer, autoimmune disorders, and neurodegenerative diseases. Consequently, a selective and universally applicable technique for the degradation of these proteins in disease-relevant conditions could significantly improve human health prospects. Lysosome-targeting chimeras (LYTACs) are bifunctional degraders comprising of an antibody conjugated with a cell–surface receptor ligand that enables cargo lysosome shuttling and degradation. Herein, we demonstrate that conjugation of antibodies with a small ketoboronate-based, lysine-reactive, covalent-reversible uptake tag (KB) enables the internalization of plasma membrane and extracellular proteins, directing them to lysosomal degradation via receptor-mediated endocytosis. Chemoproteomic target deconvolution revealed that reversible modification of lysine residues on the transferrin receptor protein 1 (TFRC) and HLA class I histocompatibility antigen A, B and C (HLA-ABC) enabled efficient uptake and lysosomal targeting through both clathrin-dependent and -independent mechanisms. KB-antibody conjugates (KB-TACs) efficiently degrade the epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor 2 (HER2) in cancer cells. Furthermore, we showed KB-TTZ degrades HER2 in vivo in BT-474 tumor xenografts, with a significant reduction in tumor volumes compared to TTZ and vehicle treatments. Altogether, the KB tag represents a versatile, minimal-size chemical unit to functionalize therapeutic antibodies for targeted protein degradation through dual receptor-mediated endocytosis and lysosomal delivery.