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

Abstract:

: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.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

Wang Y,Tang J,Wang Z,Geraghty RJ

doi

10.1016/j.antiviral.2018.01.015

subject

Has Abstract

pub_date

2018-04-01 00:00:00

pages

10-17

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(17)30692-7

journal_volume

152

pub_type

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