Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes

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

doi:10.1021/ja807921k

Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes

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

^*Corresponding author for this work

Imaging Chemistry & Biology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	3416-3417
Number of pages	2
Journal	Journal of the American Chemical Society
Volume	131
Issue number	10
DOIs	https://doi.org/10.1021/ja807921k
Publication status	Published - 18 Mar 2009

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Khan, A., Nicholson, G., Greenman, J., Madden, L., McRobbie, G., Pannecouque, C., De Clercq, E., Ullom, R., Maples, D. L., Maples, R. D., Silversides, J. D., Hubin, T. J., & Archibald, S. 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

@article{f91a89dfa59f4868b0cc65ac9977eecc,

title = "Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes",

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.",

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

year = "2009",

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doi = "10.1021/ja807921k",

language = "English",

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Khan, A, Nicholson, G, Greenman, J, Madden, L, McRobbie, G, Pannecouque, C, De Clercq, E, Ullom, R, Maples, DL, Maples, RD, Silversides, JD, Hubin, TJ & Archibald, SJ 2009, 'Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes', Journal of the American Chemical Society, vol. 131, no. 10, pp. 3416-3417. https://doi.org/10.1021/ja807921k

TY - JOUR

T1 - Binding optimization through coordination chemistry

T2 - CXCR4 chemokine receptor antagonists from ultrarigid metal complexes

AU - Khan, Abid

AU - Nicholson, Gary

AU - Greenman, John

AU - Madden, Leigh

AU - McRobbie, Graeme

AU - Pannecouque, Christophe

AU - De Clercq, Erik

AU - Ullom, Robert

AU - Maples, Danny L.

AU - Maples, Randall D.

AU - Silversides, Jon D.

AU - Hubin, Timothy J.

AU - Archibald, Stephen J.

PY - 2009/3/18

Y1 - 2009/3/18

N2 - 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.

AB - 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.

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U2 - 10.1021/ja807921k

DO - 10.1021/ja807921k

M3 - Article

C2 - 19231846

AN - SCOPUS:70249133380

SN - 0002-7863

VL - 131

SP - 3416

EP - 3417

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 10

ER -

Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes

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