Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization

Tianyu He, Tiffany Edwards, Ryuichi Majima, Eunkyung Jung, Jayakanth Kankanala, Jiashu Xie, Robert J. Geraghty, Zhengqiang (ZQ) Wang

Research output: Contribution to journalArticlepeer-review

Abstract

The terminase complex of human cytomegalovirus (HCMV) is required for viral genome packaging and cleavage. Critical to the terminase functions is a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We have previously reported metal-chelating N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human immunodeficiency virus 1 (HIV-1) RNase H. In the current work, we have synthesized new analogs and resynthesized known analogs of two isomeric HtPD subtypes, anti-HtPD (13), and syn-HtPD (14), and characterized them as inhibitors of pUL89-C. Remarkably, the vast majority of analogs strongly inhibited pUL89-C in the biochemical endonuclease assay, with IC50 values in the nM range. In the cell-based antiviral assay, a few analogs inhibited HCMV in low μM concentrations. Selected analogs were further characterized in a biophysical thermal shift assay (TSA) and in silico molecular docking, and the results support pUL89-C as the protein target of these inhibitors. Collectively, the biochemical, antiviral, biophysical, and in silico data reported herein indicate that the isomeric HtPD chemotypes 13–14 can serve as valuable chemical platforms for designing improved inhibitors of HCMV pUL89-C.

Original languageEnglish (US)
Article number106198
JournalBioorganic Chemistry
Volume129
DOIs
StatePublished - Dec 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Elsevier Inc. All rights reserved.

Keywords

  • Endonuclease
  • Human cytomegalovirus
  • Inhibitor
  • N-hydroxy thienopyrimidine-2,4-diones (HtPD)
  • pUL89-C

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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