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  • Probing the HIV-1 NCp7 nucleocapsid protein with site-specific gold(I)-phosphine complexes

    Author(s)
    de Paiva, Raphael EF
    Du, Zhifeng
    Peterson, Erica J
    Corbi, Pedro P
    Farrell, Nicholas P
    Griffith University Author(s)
    Farrell, Nicholas
    Year published
    2017
    Metadata
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    Abstract
    In this work, we examined a series of thiophilic Au(I) compounds based on [Au(L)(PR3)] (L = Cl–, 4-dimethylaminopyridine (dmap); R= ethyl (Et), cyclohexyl (Cy)) for chemoselective auration of the C-terminal HIV nucleocapsid protein NCp7 F2 and the “full” HIV NCp7 (NC, zinc finger (ZnF)) as probes of nucleocapsid topography. The choice of phosphine allowed electronic and steric effects to be considered. The use of the heterocycle “leaving group” allowed us to study the effect of possible π-stacking with the essential tryptophan residue of NC on the reactivity and selectivity, mimicking the naturally occurring interaction ...
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    In this work, we examined a series of thiophilic Au(I) compounds based on [Au(L)(PR3)] (L = Cl–, 4-dimethylaminopyridine (dmap); R= ethyl (Et), cyclohexyl (Cy)) for chemoselective auration of the C-terminal HIV nucleocapsid protein NCp7 F2 and the “full” HIV NCp7 (NC, zinc finger (ZnF)) as probes of nucleocapsid topography. The choice of phosphine allowed electronic and steric effects to be considered. The use of the heterocycle “leaving group” allowed us to study the effect of possible π-stacking with the essential tryptophan residue of NC on the reactivity and selectivity, mimicking the naturally occurring interaction between the zinc finger and nucleic acids. We also examined for comparison the “standard” gold–phosphine compound auranofin, which contains an S-bound glucose coordinated to the {Au(PEt3)} moiety. Both the nature of the phosphine and the nature of L affect the reactivity with the C-terminal NCp7 F2 and the “full” NC. 31P NMR spectroscopy showed the formation of long-lived {Au(PR3)}–ZnF species in all cases, but in the case of NCp7 F2, a selective interaction in the presence of the dmap ligand was observed. In the case of auranofin, an unusual Au–His (rather than Au–Cys) coordination was indicated on NC. The overall results suggest that it is useful to consider three aspects of zinc finger structure in considering the profile of chemical reactivity: (i) the zinc-bound cysteines as primary nucleophiles; (ii) the zinc-bound histidine as a “spectator” ligand; and (iii) ancillary groups not bound to Zn but essential for ZnF function such as the essential tryptophan in NCp7 F2 and NC. Modification of fully functional NC zinc finger by the Cy3P-containing species confirmed the inhibition of the NC–SL2 DNA interaction, as evaluated by fluorescence polarization.
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    Journal Title
    Inorganic Chemistry
    Volume
    56
    Issue
    20
    DOI
    https://doi.org/10.1021/acs.inorgchem.7b01762
    Subject
    Inorganic chemistry
    Physical chemistry
    Other chemical sciences
    Science & Technology
    Physical Sciences
    Chemistry, Inorganic & Nuclear
    Chemistry
    ACID CHAPERONE ACTIVITY
    Publication URI
    http://hdl.handle.net/10072/409773
    Collection
    • Journal articles

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