Benzimidazole-D-ribonucleosides as antiviral agents that target HCMV terminase

Abstract

Human cytomegalovirus (HCMV), one of eight human herpesviruses, can cause life-threatening diseases. HCMV is widespread throughout the population world wide; the seroprevalence in adults varies from 50-100%. HCMV infection is rarely of significant consequence in individuals with a competent immune system. However, although immune control is efficient, it cannot achieve clearance of the virus. HCMV persists lifelong in the infected host and reactivates causing reinfection. In neonates as well as in immunocompromised adults, HCMV is a serious pathogen that can cause fatal organ damage. Different antiviral compounds alone or in combination have been used for treatment of CMV diseases. Nearly all currently available drugs are targeted to the viral DNA polymerase. In clinical use, mutations in the viral DNA polymerase confer resistance to ganciclovir, foscarnet and cidofovir. We have previously provided evidence that the terminase subunits pUL56 and pUL89 as well as the portal protein pUL104 fulfill all requirements for a target of new antiviral therapy. Herein we review the development of benzimidazole-D-ribonucleosides as antiviral drugs and describe their effect on the HCMV terminase as well as on pUL104.