Structure and dynamics of metallo-macrocyles: recognition of a viral co-receptor by zinc bicyclam

J.A. Parkinson, M. Weishaupl, X. Liang, R.O. Gould, S.J. Paisley, H. Park, T.M. Hunter, S. Parsons, P.J. Sadler

Research output: Contribution to journalArticle

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Abstract

As platforms for the design of metal-based therapeutic and diagnostic agents, macrocycles are rigid enough to provide strong metal binding sites and orient functional groups stereoselectively, yet flexible enough to accommodate structural changes required for induced-fit recognition of biological targets. We consider the recognition of the Zn(II) complex of the bis-tetraazamacrocycle xylyl-bicyclam, a potent anti-HIV agent, by the coreceptor CXCR4, a G-protein-coupled receptor used by HIV for membrane fusion and cell entry. NMR studies show that the macrocycles of Zn(II)2−xylyl-bicyclam perchlorate exist in aqueous solution as two major configurations, trans-I (nitrogen chirality R,S,R,S), and trans-III (S,S,R,R). Acetate addition induced a major structural change. X-ray crystallography shows that the acetate complex contains the unusual cis-V cyclam configuration (R,R,R,R and folded) with bidentate coordination of acetate to Zn(II) plus second-coordination-sphere double H-bond formation between diagonal NH protons on the opposite cyclam face and acetate carboxylate oxygens. Detailed 1D and 2D NMR studies show that the major configuration of Zn(II)2−xylyl-bicyclam acetate in aqueous solution is cis-V/trans-I. Molecular modeling shows that an analogous cis-V site can be formed when Zn(II)2−xylyl-bicyclam binds to CXCR4, involving the carboxylate groups of Asp262 (Zn(II) coordination) and Glu288 (double H-bonding). The second cyclam can adopt the trans-I (or trans-III) configuration with Zn(II) binding to Asp171. These interactions are consistent with the known structure−activity relationships for bicyclam anti-HIV activity and receptor mutation. Consideration of the anti-HIV activity of xylyl-bicyclam complexes of other metal ions suggests that affinity for carboxylates, configurational flexibility, and kinetic factors may all play roles in receptor recognition. For example, Pd(II) cyclam complexes interact only weakly with axial ligands and are inflexible and inactive, whereas Co(III) cyclams bind carboxylates strongly, are configurationally flexible, and yet have low activity. Our findings should aid the design of new generations of active macrocycles including highly specific chemokine receptor antagonists.
LanguageEnglish
Pages9105-9112
Number of pages8
JournalJournal of the American Chemical Society
Volume124
Issue number31
DOIs
Publication statusPublished - 2002

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Zinc
Nuclear magnetic resonance
Acetates
Molecular modeling
Chirality
X ray crystallography
Binding sites
Metals
Functional groups
Metal ions
Protons
Fusion reactions
Ligands
Nitrogen
Proteins
Membranes
Hydrogen
Kinetics
Oxygen
Macrocyclic Lactams

Keywords

  • macrocycles
  • metallo-macrocyles
  • zinc bicyclam

Cite this

Parkinson, J.A. ; Weishaupl, M. ; Liang, X. ; Gould, R.O. ; Paisley, S.J. ; Park, H. ; Hunter, T.M. ; Parsons, S. ; Sadler, P.J. / Structure and dynamics of metallo-macrocyles: recognition of a viral co-receptor by zinc bicyclam. In: Journal of the American Chemical Society. 2002 ; Vol. 124, No. 31. pp. 9105-9112.
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Parkinson, JA, Weishaupl, M, Liang, X, Gould, RO, Paisley, SJ, Park, H, Hunter, TM, Parsons, S & Sadler, PJ 2002, 'Structure and dynamics of metallo-macrocyles: recognition of a viral co-receptor by zinc bicyclam' Journal of the American Chemical Society, vol. 124, no. 31, pp. 9105-9112. https://doi.org/10.1021/ja0260723

Structure and dynamics of metallo-macrocyles: recognition of a viral co-receptor by zinc bicyclam. / Parkinson, J.A.; Weishaupl, M.; Liang, X.; Gould, R.O.; Paisley, S.J.; Park, H.; Hunter, T.M.; Parsons, S.; Sadler, P.J.

In: Journal of the American Chemical Society, Vol. 124, No. 31, 2002, p. 9105-9112.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure and dynamics of metallo-macrocyles: recognition of a viral co-receptor by zinc bicyclam

AU - Parkinson, J.A.

AU - Weishaupl, M.

AU - Liang, X.

AU - Gould, R.O.

AU - Paisley, S.J.

AU - Park, H.

AU - Hunter, T.M.

AU - Parsons, S.

AU - Sadler, P.J.

PY - 2002

Y1 - 2002

N2 - As platforms for the design of metal-based therapeutic and diagnostic agents, macrocycles are rigid enough to provide strong metal binding sites and orient functional groups stereoselectively, yet flexible enough to accommodate structural changes required for induced-fit recognition of biological targets. We consider the recognition of the Zn(II) complex of the bis-tetraazamacrocycle xylyl-bicyclam, a potent anti-HIV agent, by the coreceptor CXCR4, a G-protein-coupled receptor used by HIV for membrane fusion and cell entry. NMR studies show that the macrocycles of Zn(II)2−xylyl-bicyclam perchlorate exist in aqueous solution as two major configurations, trans-I (nitrogen chirality R,S,R,S), and trans-III (S,S,R,R). Acetate addition induced a major structural change. X-ray crystallography shows that the acetate complex contains the unusual cis-V cyclam configuration (R,R,R,R and folded) with bidentate coordination of acetate to Zn(II) plus second-coordination-sphere double H-bond formation between diagonal NH protons on the opposite cyclam face and acetate carboxylate oxygens. Detailed 1D and 2D NMR studies show that the major configuration of Zn(II)2−xylyl-bicyclam acetate in aqueous solution is cis-V/trans-I. Molecular modeling shows that an analogous cis-V site can be formed when Zn(II)2−xylyl-bicyclam binds to CXCR4, involving the carboxylate groups of Asp262 (Zn(II) coordination) and Glu288 (double H-bonding). The second cyclam can adopt the trans-I (or trans-III) configuration with Zn(II) binding to Asp171. These interactions are consistent with the known structure−activity relationships for bicyclam anti-HIV activity and receptor mutation. Consideration of the anti-HIV activity of xylyl-bicyclam complexes of other metal ions suggests that affinity for carboxylates, configurational flexibility, and kinetic factors may all play roles in receptor recognition. For example, Pd(II) cyclam complexes interact only weakly with axial ligands and are inflexible and inactive, whereas Co(III) cyclams bind carboxylates strongly, are configurationally flexible, and yet have low activity. Our findings should aid the design of new generations of active macrocycles including highly specific chemokine receptor antagonists.

AB - As platforms for the design of metal-based therapeutic and diagnostic agents, macrocycles are rigid enough to provide strong metal binding sites and orient functional groups stereoselectively, yet flexible enough to accommodate structural changes required for induced-fit recognition of biological targets. We consider the recognition of the Zn(II) complex of the bis-tetraazamacrocycle xylyl-bicyclam, a potent anti-HIV agent, by the coreceptor CXCR4, a G-protein-coupled receptor used by HIV for membrane fusion and cell entry. NMR studies show that the macrocycles of Zn(II)2−xylyl-bicyclam perchlorate exist in aqueous solution as two major configurations, trans-I (nitrogen chirality R,S,R,S), and trans-III (S,S,R,R). Acetate addition induced a major structural change. X-ray crystallography shows that the acetate complex contains the unusual cis-V cyclam configuration (R,R,R,R and folded) with bidentate coordination of acetate to Zn(II) plus second-coordination-sphere double H-bond formation between diagonal NH protons on the opposite cyclam face and acetate carboxylate oxygens. Detailed 1D and 2D NMR studies show that the major configuration of Zn(II)2−xylyl-bicyclam acetate in aqueous solution is cis-V/trans-I. Molecular modeling shows that an analogous cis-V site can be formed when Zn(II)2−xylyl-bicyclam binds to CXCR4, involving the carboxylate groups of Asp262 (Zn(II) coordination) and Glu288 (double H-bonding). The second cyclam can adopt the trans-I (or trans-III) configuration with Zn(II) binding to Asp171. These interactions are consistent with the known structure−activity relationships for bicyclam anti-HIV activity and receptor mutation. Consideration of the anti-HIV activity of xylyl-bicyclam complexes of other metal ions suggests that affinity for carboxylates, configurational flexibility, and kinetic factors may all play roles in receptor recognition. For example, Pd(II) cyclam complexes interact only weakly with axial ligands and are inflexible and inactive, whereas Co(III) cyclams bind carboxylates strongly, are configurationally flexible, and yet have low activity. Our findings should aid the design of new generations of active macrocycles including highly specific chemokine receptor antagonists.

KW - macrocycles

KW - metallo-macrocyles

KW - zinc bicyclam

U2 - 10.1021/ja0260723

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EP - 9112

JO - Journal of the American Chemical Society

T2 - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

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