Binding Optimization through Coordination Chemistry: CXCR4 Chemokine Receptor Antagonists from Ultrarigid Metal Complexes

Khan, Abid; Nicholson, Gary; McRobbie, Graeme; Pannecouque, Christophe; De Clercq, Erik; Ullom, Robert; Maples, Danny L.; Maples, Randall D.; Silversides, Jon D.; Hubin, Timothy J.; Archibald, Stephen J.; Madden, Leigh; Greenman, John

Abstract

A new copper(II) containing bis-macrocyclic CXCR4 chemokine receptor antagonist is shown to have improved binding properties to the receptor protein in comparison to the drug AMD3100 (Plerixafor, Mozobil). The interaction of the metallodrug has been optimized by using ultrarigid chelator units that offer an equatorial site for coordination to the amino acid side chains of the protein. Binding competition assays with anti-CXCR4 antibodies show that the new compound stays bound longer and it has improved anti-HIV potency in vitro (EC 50 = 4.3 nM). X-ray structural studies using acetate as a model for carboxylate amino acid side chains indicate the nature of the coordination interaction. Copyright © 2009 American Chemical Society.

Citation

Khan, A., Nicholson, G., McRobbie, G., Pannecouque, C., De Clercq, E., Ullom, R., Maples, D. L., Maples, R. D., Silversides, J. D., Hubin, T. J., Archibald, S. J., Madden, L., & Greenman, J. (2009). Binding Optimization through Coordination Chemistry: CXCR4 Chemokine Receptor Antagonists from Ultrarigid Metal Complexes. Journal of the American Chemical Society, 131(10), 3416-3417. https://doi.org/10.1021/ja807921k

• Journal Article Type: Article
• Acceptance Date: Mar 18, 2009
• Publication Date: Feb 18, 2009
• Journal: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• Print ISSN: 0002-7863
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 131
• Issue: 10
• Pages: 3416-3417
• DOI: https://doi.org/10.1021/ja807921k
• Keywords: Colloid and Surface Chemistry; Biochemistry; General Chemistry; Catalysis
• Public URL: https://hull-repository.worktribe.com/output/391464