Abstract
Viral polymerases are important targets in drug discovery and development efforts. Most antiviral compounds that are currently approved for treatment of infection with members of the herpesviridae family were shown to inhibit the viral DNA polymerase. However, biochemical studies that shed light on mechanisms of drug action and resistance are hampered primarily due to technical problems associated with enzyme expression and purification. In contrast, the orthologous bacteriophage RB69 polymerase gp43 has been crystallized in various forms and therefore serves as a model system that provides a better understanding of structure–function relationships of polymerases that belong the type B family. This review aims to discuss strengths, limitations, and opportunities of the phage surrogate with emphasis placed on its utility in the discovery and development of anti-herpetic drugs.
Highlights
The eukaryotic viruses of the herpesviridae family are important human pathogens
Protein sequence alignments of Herpes simplex virus 1 and 2 (HSV1) UL30 to other herpesviridae DNA polymerase show that it is likely that all Human herpesviridae DNA polymerases contain a pre-N terminal domain [9]
Catalytic Cycle of B Type Polymerase RB69gp43. Both RB69gp43 and HSV1 UL30 have been crystallized in the so-called open conformation [9,13], but only RB69 has been crystallized in the closed conformation [15]
Summary
The eukaryotic viruses of the herpesviridae family are important human pathogens. In all, there are eight different human herpesviruses; Herpes simplex virus 1 and 2 (HSV1: HHV1 and HSV2: HHV2), varicella zoster virus (VZV: HHV3), Epstein-Barr virus (EBV: HHV4), Human cytomegalovirus (HCMV: HHV5), Human Herpes virus 6 and 7 (HHV6 and HHV7) and Kaposi’s sarcoma-associated herpesvirus (KSHV, HHV8). Viruses that belong to the herpesviridae family are characterized by their ability to establish lifelong, latent infections. Of the eight human herpesvirus DNA polymerases, the best-studied is perhaps UL30 from HSV1. This enzyme has been characterized extensively biochemically and has been successfully crystallized [9]. RB69gp has been crystallized in various forms and provides an important structural model for polymerases that belong to the same family [13,14,15,16]. It is here attempted to discuss the general aspects of structure and function of these related enzymes and the utility of RB69gp as a surrogate system for herpesviridae DNA polymerases in efforts to provide a better understanding of mechanisms of drug action and resistance
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