The herpesvirus proteases as targets for antiviral chemotherapy

Viruses of the family Herpesviridae are responsible for a diverse set of hu man diseases. The available treatments are largely ineffective, with the ex ception of a few drugs for treatment of herpes simplex virus (HSV) infectio ns. For several members of this DNA virus family, advances have been made r ecently in the biochemistry and structural biology of the essential viral p rotease, revealing common features that may be possible to exploit in the d evelopment of a new class of anti-herpesvirus agents. The herpesvirus prote ases have been identified as belonging to a unique class of serine protease , with a Ser-His-His catalytic triad. A new, single domain protein fold has been determined by X-ray crystallography for the proteases of at least thr ee different herpesviruses. Also unique for serine proteases, dimerization has been shown to be required for activity of the cytomegalovirus and HSV p roteases. The dimerization requirement seriously impacts methods needed for productive, functional analysis and inhibitor discovery. The conserved fun ctional and catalytic properties of the herpesvirus proteases lead to commo n considerations for this group of proteases in the early phases of inhibit or discovery. In general, classical serine protease inhibitors that react w ith active site residues do not readily inactivate the herpesvirus protease s. There has been progress however, with activated carbonyls that exploit t he selective nucleophilicity of the active site serine. In addition, screen ing of chemical libraries has yielded novel structures as starting points f or drug development. Recent crystal structures of the herpesvirus proteases now allow more direct interpretation of ligand structure-activity relation ships. This review first describes basic functional aspects of herpesvirus protease biology and enzymology. Then we discuss inhibitors identified to d ate and the prospects for their future development.