Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replication

Yan Wang, Jing Tang, Zhengqiang Wang, Robert J. Geraghty

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus production. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compounds featuring a chelating triad motif. Previously, we developed a novel ELISA approach to screen for pUL89 inhibitors. In this report, we used the ELISA to identify 3-hydroxypyrimidine-2,4-dione as a promising scaffold for pUL89 inhibitor development. Several potent pUL89 inhibitors yielded low micromolar IC50 values in the enzymatic assay and low micromolar EC50 values for inhibition of HCMV replication. Two representative compounds inhibitory effects depended upon metal ions and occurred late in virus replication consistent with pUL89 inhibitors in infected cells.

Original languageEnglish (US)
Pages (from-to)10-17
Number of pages8
JournalAntiviral Research
StatePublished - Apr 2018

Bibliographical note

Funding Information:
We thank Wade Bresnahan, University of Minnesota, for providing reagents. This work was supported by the Center for Drug Design at the University of Minnesota .

Publisher Copyright:
© 2018 Elsevier B.V.


  • 3-Hydroxypyrimidine-2,4-dione
  • Human cytomegalovirus
  • Terminase inhibitor
  • UL89


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