The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design

Abstract

Vast evolutionary distances separate the known herpesviruses, adapted to colonise specialised cells in predominantly vertebrate hosts. Nevertheless, the distinct herpesvirus families share recognisably related genomic attributes. The taxonomic Family Herpesviridae includes many important human and animal pathogens. Successful antiviral drugs targeting Herpesviridae are available, but the need for reduced toxicity and improved efficacy in critical healthcare interventions invites novel solutions: immunocompromised patients presenting particular challenges. A conserved enzyme required for viral fitness is Ung, a uracil-DNA glycosylase, which is encoded ubiquitously in Herpesviridae genomes and also host cells. Research investigating Ung in Herpesviridae dynamics has uncovered an unexpected combination of viral co-option of host Ung, along with remarkable Subfamily-specific exaptation of the virus-encoded Ung. These enzymes apparently play essential roles, both in the maintenance of viral latency and during initiation of lytic replication. The ubiquitously conserved Ung active site has previously been explored as a therapeutic target. However, exquisite selectivity and better drug-like characteristics might instead be obtained via targeting structural variations within another motif of catalytic importance in Ung. The motif structure is unique within each Subfamily and essential for viral survival. This unique signature in highly conserved Ung constitutes an attractive exploratory target for the development of novel beneficial therapeutics.