Design and characterization of an intracellular covalent ligand for CC chemokine receptor 2
| Autor: | Adriaan P. IJzerman, Daan van der Es, Emy Theunissen, Laura H. Heitman, Natalia V. Ortiz Zacarías, Lloyd Mallee, Tracy M. Handel, Yi Zheng, Irina Kufareva, Tereza Šimková, Cas van der Horst, Asuka Inoue, Julien Louvel, Kirti Kandhwal Chahal |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CCR2
Receptors CCR2 In silico CHO Cells Plasma protein binding Peptides and proteins Ligands 01 natural sciences Assays 03 medical and health sciences Cricetulus Cell Line Tumor parasitic diseases Drug Discovery Receptors Animals Humans Cysteine Binding site 030304 developmental biology G protein-coupled receptor Sulfonamides 0303 health sciences Binding Sites Ligand Chemistry Monomers 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry HEK293 Cells Biochemistry Covalent bond Drug Design Mutation Mutagenesis Site-Directed Molecular Medicine CC chemokine receptors Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry, 64(5), 2608-2621. American Chemical Society (ACS) Journal of Medicinal Chemistry |
| Popis: | Covalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we aimed to develop a covalent antagonist of CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a therapeutic target in inflammation and immuno-oncology. Based on a known intracellularly binding CCR2 antagonist, several covalent derivatives were synthesized and characterized by radioligand binding and functional assays. These studies revealed compound 14 as an intracellular covalent ligand for CCR2. In silico modeling followed by site-directed mutagenesis confirmed that 14 forms a covalent bond with one of three proximal cysteine residues, which can be engaged interchangeably. To our knowledge, compound 14 represents the first covalent ligand reported for CCR2. Due to its unique properties, it may represent a promising tool for ongoing and future studies of CCR2 pharmacology. |
| Databáze: | OpenAIRE |
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