Strathprints Home | Open Access | Browse | Search | User area | Copyright | Help | Library Home | SUPrimo

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

Parkinson, J.A. and Weishaupl, M. and Liang, X. and Gould, R.O. and Paisley, S.J. and Park, H. and Hunter, T.M. and Parsons, S. and Sadler, P.J. (2002) Structure and dynamics of metallo-macrocyles: recognition of a viral co-receptor by zinc bicyclam. Journal of the American Chemical Society, 124 (31). pp. 9105-9112.

Full text not available in this repository. (Request a copy from the Strathclyde author)

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.

Item type: Article
ID code: 38588
Keywords: macrocycles , metallo-macrocyles , zinc bicyclam, Chemistry
Subjects: Science > Chemistry
Department: Faculty of Science > Pure and Applied Chemistry
Faculty of Science > Institute of Photonics
Related URLs:
    Depositing user: Pure Administrator
    Date Deposited: 20 Mar 2012 12:16
    Last modified: 16 Jul 2013 21:29
    URI: http://strathprints.strath.ac.uk/id/eprint/38588

    Actions (login required)

    View Item