Liang, Xiangyang, Parkinson, J. A. (John A.), Weishäupl, Michael, Gould, Robert O., Paisey, Stephen J., Park, Hye-seo, Hunter, Tina M., Blindauer, Claudia A., Parsons, S. (Simon) and Sadler, P. J. (2002) Structure and dynamics of metallomacrocycles : recognition of zinc xylyl-bicyclam by an HIV coreceptor. Journal of the American Chemical Society, Vol.124 (No.31). pp. 9105-9112. doi:10.1021/ja0260723

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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(11)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(11)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(11)(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 Asp-171. 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(Ill) 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.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Metal complexes -- Therapeutic use, Macrocyclic compounds, HIV (Viruses), Zinc compounds -- Therapeutic use, Chemokines -- Receptors, Binding sites (Biochemistry), Structure-activity relationships (Biochemistry)
Journal or Publication Title:	Journal of the American Chemical Society
Publisher:	American Chemical Society
ISSN:	0002-7863
Official Date:	7 August 2002
Dates:	Date Event 7 August 2002 Published
Volume:	Vol.124
Number:	No.31
Page Range:	pp. 9105-9112
DOI:	10.1021/ja0260723
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Wellcome Trust (London, England), Engineering and Physical Sciences Research Council (EPSRC), European Commission (EC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Royal Society (Great Britain), Wolfson Foundation, Deutsche Forschungsgemeinschaft (DFG)

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