Structure and dynamics of metallomacrocycles: recognition of zinc xylyl-bicyclam by an HIV coreceptor

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.     

STUDIES OF ADHESION OF METAL PARTICLES TO SILICA PARTICLES BASED ON ZETA POTENTIAL MEASUREMENTS

The zeta-potentials of silica, copper, platinum and gold particles have been measured as a function of pH. The isoelectric points were found to be at pH 3.0, 5.8, 3.0 and 3.5, respectively. In the pH range 3.0 to 5.8 copper and silica particles are oppositely charged and accordingly the coating of silica with copper particles could be demonstrated. In the case of gold and platinum the sign of the charge is such that direct adhesion to silica particles cannot be expected and this was also demonstrated in the case of platinum.     

<Emphasis Type="Italic">N</Emphasis>-arachidonoyl glycine,an abundant endogenous lipid,potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor

Background  

Microglia provide continuous immune surveillance of the CNS and upon activation rapidly change phenotype to express receptors that respond to chemoattractants during CNS damage or infection. These activated microglia undergo directed migration towards affected tissue. Importantly, the molecular species of chemoattractant encountered determines if microglia respond with pro- or anti-inflammatory behaviour, yet the signaling molecules that trigger migration remain poorly understood. The endogenous cannabinoid system regulates microglial migration via CB₂ receptors and an as yet unidentified GPCR termed the 'abnormal cannabidiol' (Abn-CBD) receptor. Abn-CBD is a synthetic isomer of the phytocannabinoid cannabidiol (CBD) and is inactive at CB₁ or CB₂ receptors, but functions as a selective agonist at this G_i/o-coupled GPCR. N-arachidonoyl glycine (NAGly) is an endogenous metabolite of the endocannabinoid anandamide and acts as an efficacious agonist at GPR18. Here, we investigate the relationship between NAGly, Abn-CBD, the unidentified 'Abn-CBD' receptor, GPR18, and BV-2 microglial migration.     

Anti-viral cyclam macrocycles : rapid zinc uptake at physiological pH

NMR and UV-vis spectroscopic studies show that Zn(II) binds to cyclam rapidly at micromolar concentrations, an observation relevant to the anti-viral activity and co-receptor binding of anti-HIV cyclams.     

Set the controls for the heart of the Sun

In this paper we describe experiments conducted with high-power lasers that are attempting to replicate, for a very short time and in miniature, conditions found in the Sun. Experiments to date have reached conditions in the outer part of the Sun. To reach the Sun's centre requires compression of material to very much greater than solid density and heating to over ten million degrees. To achieve this, a new class of experiments and a new generation of high-power lasers are required.