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Affinity-guided protein conjugation: the trilogy of covalent protein labeling, assembly and inhibition

Science China Chemistry 2016年第7期59卷 853-861页

作者： Yongsheng Yu Jiang Xia Center of Novel Biomaterials Department of Chemistry Chinese University of Hong Kong

Specific and dynamic biological interactions pave the blueprint of signal networks in cell. For example, a great variety of specific protein-ligand interactions define how intracellular signals flow. Taking advantage of the specificity of these interactions, we postulate an "affinity-guided covalent conjugation" strategy to lock binding ligands through covalent reactions between the ligand and the receptor protein. The presence of a nucleophile close to the ligand binding site of a protein is sine qua none of this reaction. Specific noncovalent interaction of a ligand derivative(which contains an electrophile at a designed position) to the ligand binding site of the protein brings the electrophile to the close proximity of the nucleophile. Subsequently, a conjugation reaction spontaneously takes place between the nucleophile and the electrophile, and leads to an intermolecular covalent linkage. This strategy was first showcased in coiled coil peptides which include a cysteine mutation at a selected position. The short peptide sequence was used for covalent labeling of cell surface receptors. The same strategy was then used to guide the design of a set of protein Lego bricks for covalent assembly of protein complexes of unnatural geometry. We finally made "reactive peptides" for natural adaptor proteins that play significant roles in signal transduction. The peptides were designed to react with a single domain of the multidomain adaptor protein, delivered into the cytosol of neurons, and re-directed the intracellular signal of neuronal migration. The trilogy of protein labeling, assembly, and inhibition of intracellular signals, all through a specific covalent bond, fully demonstrated the generality and versatility of "affinity-guided covalent conjugation" in various applications.

关键词： peptide-peptide interaction covalent labeling bioconjugation reaction protein assembly inhibitor signal transduction affinity-guided reaction

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Targeted Degradation of DNA/RNA Binding Proteins via covalent Hydrophobic Tagging

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CCS Chemistry 2023年第10期5卷 2207-2214页

作者： Yan Wang Jingzi Zhang Jiafang Deng Chengzhi Wang Lei Fang Yan Zhang Jinbo Li State Key Laboratory of Analytical Chemistry for Life Sciences Jiangsu Key Laboratory of Advanced Organic MaterialsSchool of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023 Jiangsu Key Laboratory of Molecular Medicine Chemistry and Biomedicine Innovation Center(ChemBIC)Medical School of Nanjing UniversityNanjing 210093

Targeted protein degradation(TPD)holds great promise for biological inquiry and therapeutic ***,it still remains elusive to destruct DNA/RNA binding proteins(DBPs/RBPs)previously deemed ***,we report ligandassisted covalent hydrophobic tagging(LACHT)as a modular strategy for TPD of these difficult-totarget *** by a noncovalent protein ligand,LACHT leverages a reactive N-acyl-N-alkyl sulfonamide group to covalently label the protein target with a hydrophobic adamantane,which further engages the cellular quality control mechanism to induce proteolytic *** a smallmolecule ligand,we demonstrated that LACHT allowed TPD of a DBP,bromodomain-containing protein 4,in human leukemia cells with high *** studies revealed that LACHT-mediated TPD dependent on ligand-directed irreversible tagging and the covalently labeled proteins underwent polyubiquitination before removal through both the proteasome and the ***,when an RNA ligand was employed,we showed that LACHT also enabled TPD of an RBP,Lin28a,leading to upregulation of its downstream let-7 *** study thus provides a generalizable platform to expand the TPD toolbox for biomedical applications.

关键词： targeted protein degradation covalent labeling hydrophobic tagging DNA/RNA binding proteins miRNA

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