Anti-HIV agents that selectively target the retroviral nucleocapsid protein zinc fingers without affecting cellular zinc finger proteins

A product of the AIDS drug discovery and development initiative of the National Cancer Institute has been the identification of the HIV-1 nucleocapsid p7 (NCp7) protein Zn fingers as prime targets for antiviral therapy and discovery of a process for chemically modifying those structures. A vast number of compounds have been identified that covalently modify the nucleophilic sulfur atoms of the Zn-coordinating Cys residues of the Zn finger domains, yet studies to date have not documented selectivity of these compounds for the retroviral Zn finger domains over other types of Zn fingers. We now show that three separate chemotypes can promote Zn ejection from NCp7 Zn fingers and lead to changes in protein structure and loss of nucleic acid binding capacity at concentrations that do not affect the activities of other Zn finger proteins, including the cellular poly(ADP-ribose) polymerase enzyme and the Sp1 and GATA-1 transcription factors. Molecular modeling of ligands to the NCp7 Zn fingers identified docked configurations having free energies of binding and frontier molecular orbital overlap that provide for favorable reactivities. Data suggested that these compounds target a common saddle-shaped binding domain on the surface of the fingers that can yield productive chemical reactivities. Modeling analyses also indicated that the most favorable site for electrophilic attack of NCp7 is the sulfur atom of the last Cys residue (Cys49) in the carboxy-terminal finger. These data provide the first proof and rationale for selective reactivities of compounds with the HIV-1 NCp7 Zn finger domains.

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