Inhibition of human cytomegalovirus pUL89 terminase subunit blocks virus replication and genome cleavage

Yan Wang, Lili Mao, Jayakanth Kankanala, Zhengqiang Wang, Robert J. Geraghty

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


The human cytomegalovirus terminase complex cleaves concatemeric genomic DNA into unit lengths during genome packaging and particle assembly. This process is an attractive drug target because cleavage of concatemeric DNA is not required in mammalian cell DNA replication, indicating that drugs targeting the terminase complex could be safe and selective. One component of the human cytomegalovirus terminase complex, pUL89, provides the endonucleolytic activity for genome cleavage, and the domain responsible is reported to have an RNase H-like fold. We hypothesize that the pUL89 endonuclease activity is inhibited by known RNase H inhibitors. Using a novel enzyme-linked immunosorbent assay (ELISA) format as a screening assay, we found that a hydroxypyridonecarboxylic acid compound, previously reported to be an inhibitor of human immunodeficiency virus RNase H, inhibited pUL89 endonuclease activity at low-micromolar concentrations. Further characterization revealed that this pUL89 endonuclease inhibitor blocked human cytomegalovirus replication at a relatively late time point, similarly to other reported terminase complex inhibitors. Importantly, this inhibitor also prevented the cleavage of viral genomic DNA in infected cells. Taken together, these results substantiate our pharmacophore hypothesis and validate our ligand-based approach toward identifying novel inhibitors of pUL89 endonuclease.

Original languageEnglish (US)
Article numbere02152-16
JournalJournal of virology
Issue number3
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017 American Society for Microbiology. All Rights Reserved.


  • Human cytomegalovirus
  • Hydroxypyridonecarboxylic acid
  • Metal chelation
  • PUL89 inhibitor
  • Terminase


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