Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2

Natalia V. Ortiz Zacarías, Kirti K. Chahal, Tereza Šimková, Cas Van Der Horst, Yi Zheng, Asuka Inoue, Emy Theunissen, Lloyd Mallee, Daan Van Der Es, Julien Louvel, Adriaan P. Ijzerman, Tracy M. Handel, Irina Kufareva, Laura H. Heitman

研究成果: Article査読

1 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)2608-2621
ページ数14
ジャーナルJournal of Medicinal Chemistry
64
5
DOI
出版ステータスPublished - 2021 3 11

ASJC Scopus subject areas

  • 分子医療
  • 創薬

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