ANTI-HIV AGENTS THAT SELECTIVELY TARGET RETROVIRAL NUCLEOCAPSID PROTEIN ZINC FINGERS WITHOUT AFFECTING CELLULAR ZINC-FINGER PROTEINS

Agents that target the two highly conserved Zn fingers of the human im munodeficiency virus (HIV) nucleocapsid p7 (NCp7) protein are under de velopment as antivirals. These agents covalently modify Zn-coordinatin g cysteine thiolates of the fingers, causing Zn ejection, loss of nati ve protein structure and nucleic acid binding capacity, and disruption of virus replication. Concentrations of three antiviral agents that p romoted in vitro Zn ejection from NCp7 and inhibited HIV replication d id not impact the functions of cellular Zn finger proteins, including poly(ADP-ribose) polymerase and the Spl and GATA-1 transcription facto rs, nor did the compounds inhibit HeLa nuclear extract mediated transc ription. Selectivity of interactions of these agents with NCp7 was sup ported by molecular modeling analysis which (1) identified a common sa ddle-shaped nucleophilic region on the surfaces of both NCp7 Zn finger s, (2) indicated a strong correspondence between computationally docke d positions for the agents tested and overlap of frontier orbitals wit hin the nucleophilic loci of the NCp7 Zn fingers, and (3) revealed sel ective steric exclusion of the agents from the core of the GATA-1 Zn f inger. Further modeling analysis suggests that the thiolate of Cys49 i n the carboxy-terminal finger is the site most susceptible to electrop hilic attack. These data provide the first experimental evidence and r ationale for antiviral agents that selectively target retroviral nucle ocapsid protein Zn fingers.