| Human cytomegalovirus (HCMV) is the largest known human herpesvirus, and a ubiquitous pathogen, infecting the majority of the population. Infections of immuno-compromised individuals by HCMV results in deleterious health effects, often times death. Therefore, the development of antiviral agents against this pathogen is of great importance. HCMV encodes a protease essential for the viral life cycle, and no cellular proteases have been identified to substitute for the functional role of this enzyme. Therefore, the protease has been an intensely pursued target in the past few years for the development of antiviral agents. However, success has been limited due to the many unique biochemical properties of the protease.; The work set forth is a summary of successful studies aimed at characterizing the HCMV protease. A number of techniques have been employed for the characterization, including X-ray crystallography, site-directed mutagenesis, fluorescence kinetics, analytical ultracentrifugation (AUC), Circular Dichroism (CD), chromatography, and mass spectroscopy. These studies have helped expand the body of knowledge available for proteases, and all enzymes. In addition, these studies serve as a basis for the development of inhibitors targeting the protease. The structural homology between herpesvirus proteases allows for information obtained from HCMV protease to be conveyed to all herpesvirus proteases.; The thesis will begin with the medical relevance of HCMV infection, and continue with the importance and role of the protease in the viral life cycle (Chapter 1). Subsequent chapters will pursue studies aimed at characterizing the protease (Chapters II to V). The final chapter is a proposed mechanism in the structural role of the protease in viral capsid assembly, the event in which the activity of the protease is essential for the production of infectious viral particles. |
