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Experimental determination and calculations of redox potential descriptors of compounds directed against retroviral zinc fingers: Implications for rational drug design

¹ Advanced Biomedical Computing Center, Scientific Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA
² AIDS Vaccine Program, Scientific Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA
³ Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, Maryland 21250, USA
⁴ Structural Biochemistry Program, Scientific Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA

Reprint requests to: Louis E. Henderson, AIDS Vaccine Program, SAIC Frederick, National Cancer Institute at Frederick, Building 535, 4th Floor, P.O. Box B, Frederick, MD 21702–1124, USA; e-mail: henderson{at}avpaxp1.ncifcrf.gov; fax: 301–846–5588.

A diverse set of electrophilic compounds that react with cysteine thiolates in retroviral nucleocapsid (NC) proteins and abolish virus infectivity has been identified. Although different in chemical composition, these compounds are all oxidizing agents that lead to the ejection of Zn(II) ions bound to conserved structural motifs (zinc fingers) present in retroviral NC proteins. The reactivity of a congeneric series of aromatic disulfides toward the NC protein of the human immunodeficiency virus type 1 (HIV-1), NCp7, has been characterized by HPLC separation of starting reagents from reaction products. We calculated the absolute redox potentials of these compounds in the gas phase and in aqueous solvent, using a density functional theory method and a continuum solvation model. Pulsed polarography experiments were performed and showed a direct correlation between calculated and experimentally determined redox propensities. A dependence between protein reactivity and redox potential for a specific compound was shown: Reaction with NCp7 did not take place below a threshold value of redox potential. This relationship permits the distinction between active and nonactive compounds targeted against NCp7, and provides a theoretical basis for a scale of reactivity with retroviral zinc fingers. Our results indicate that electrophilic agents with adequate thiophilicity to react with retroviral NC fingers can now be designed using known or calculated electrochemical properties. This may assist in the design of antiretroviral compounds with greater specificity for NC protein. Such electrophilic agents can be used in retrovirus inactivation with the intent of preparing a whole-killed virus vaccine formulation that exhibits unaffected surface antigenic properties.

Keywords: Nucleocapsid; antiretroviral compounds; pulsed polarography; zinc ejection; redox potential; viral inactivation; zinc fingers; density functional theory methods

Abbreviations: AT-2, aldrithiol-2 (2,2`-dithiodipyridine) • BEM, boundary element method • BLYP, Becke-Lee-Yang-Parr exchange correlation method • DFT, density functional theory • DMSO, dimethyl sulfoxide • DZVPD, double zeta-split valence potential plus diffuse d-functions • EA, electron affinity • HIV-1, human immunodeficiency virus type 1 • HPLC, high-performance liquid chromatography • NC, nucleocapsid • NCp7, Zn(II)-bound HIV-1 nucleocapsid protein • NEM, N-ethylmaleimide • SCF, self-consistent field • QSAR, quantitative structure-activity relationship • TFA, trifluoroacetic acid

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