The search for new therapies for human cytomegalovirus infections

Abstract

Ganciclovir (GCV), the therapy of choice for human cytomegalovirus (CMV) infections and foscarnet, a drug used to treat GCV-resistant CMV infections was approved more than twenty years ago. Although cidofovir and a prodrug of GCV have since been added to the armamentarium, a highly effective drug without significant toxicities has yet to be approved. Such a therapeutic agent is required for treatment of immunocompromised hosts and infants, which bear the greatest burden of disease. The modest antiviral activity of existing drugs is insufficient to completely suppress viral replication, which results in the selection of drug-resistant variants that remain pathogenic, continue to replicate, and contribute to disease. Sustained efforts, largely in the biotech industry and academia, have identified highly active lead compounds that have progressed into clinical studies with varying levels of success. A few of these compounds inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapies. Some of the more promising drugs will be discussed with an emphasis on those progressing to clinical studies. Their antiviral activity both in vitro and in vivo, spectrum of antiviral activity, and mechanism of action will be reviewed to provide an update on the progress of potential new therapies for CMV infections.

Figure 1

Summary of compounds that inhibit various stages of CMV replication. Infection is initiated by virions that bind to receptors at the cell surface and can be prevented through the inactivation of virions by purified immunoglobulins (IVIG) or other attachment inhibitors. Several nucleoside inhibitors are capable of inhibiting the subsequent synthesis of viral DNA, including the approved therapies. The coordinated steps of genome cleavage/packaging are inhibited by three separate classes of inhibitors and prevent the stable encapsidation of nascent viral DNA. Inhibitors of the viral UL97 kinase, such as maribavir, impact both early and late events in viral replication and inhibit the egress of mature capsids into the cytoplasm.

Figure 2

Selected inhibitors of viral DNA synthesis.

Figure 3

Selected inhibitors of later steps in viral replication.