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

Topol, IA McGrath, C Chertova, E Dasenbrock, C Lacourse, WR Eissenstat, MA Burt, SK Henderson, LE Casas-Finet, JR

Ia. Topol et al., Experimental determination and calculations of redox potential descriptorsof compounds directed against retroviral zinc fingers: Implications for rational drug design, PROTEIN SCI, 10(7), 2001, pp. 1434-1445

51

INGLESE

Article

Biochemistry & Biophysics

PROTEIN SCIENCE

0961-8368 → ACNP

10

7

2001

1434 - 1445

ISI

0961-8368(200107)10:7<1434:EDACOR>2.0.ZU;2-O

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 compoun ds are all oxidizing agents that lead to the ejection of Zn(II) ions bound to conserved structural motifs (zinc fingers) present in retroviral NC prot eins. The reactivity of a congeneric series of aromatic disulfides toward t he NC protein of the human immunodeficiency virus type 1 (HIV-1), NCp7, has been characterized by HPLC separation of starting reagents from reaction p roducts. We calculated the absolute redox potentials of these compounds in the gas phase and in aqueous solvent, using a density functional theory met hod and a continuum solvation model. Pulsed polarography experiments were p erformed and showed a direct correlation between calculated and experimenta lly determined redox propensities. A dependence between protein reactivity and redox potential for a specific compound was shown: Reaction with NCp7 d id not take place below a threshold value of redox potential. This relation ship permits the distinction between active and nonactive compounds targete d against NCp7, and provides a theoretical basis for a scale of reactivity with retroviral zinc fingers. Our results indicate that electrophilic agent s with adequate thiophilicity to react with retroviral NC fingers can now b e designed using known or calculated electrochemical properties, This may a ssist in the design of antiretroviral compounds with greater specificity fo r NC protein. Such electrophilic agents can be used in retrovirus inactivat ion with the intent of preparing a whole-killed virus vaccine formulation t hat exhibits unaffected surface antigenic properties.