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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

Authors

Abid Khan

Gary Nicholson

Graeme McRobbie

Christophe Pannecouque

Erik De Clercq

Robert Ullom

Danny L. Maples

Randall D. Maples

Jon D. Silversides

Timothy J. Hubin

Leigh Madden L.A.Madden@hull.ac.uk

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.

Journal Article Type Article
Publication Date Feb 18, 2009
Journal JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Print ISSN 0002-7863
Electronic ISSN 1520-5126
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