8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease

Eunkyung Jung, Ryuichi Majima, Tiffany C. Edwards, Ruben Soto-Acosta, Robert J. Geraghty, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Human cytomegalovirus (HCMV) replication requires a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C) for viral genome packaging and cleavage. We have previously shown that pUL89-C can be pharmacologically inhibited with designed metal-chelating compounds. We report herein the synthesis of a few 8-hydroxy-1,6-naphthyridine subtypes, including 5-chloro (subtype 15), 5-aryl (subtype 16), and 5-amino (subtype 17) variants. Analogs were studied for the inhibition of pUL89-C in a biochemical endonuclease assay, a biophysical thermal shift assay (TSA), in silico molecular docking, and for the antiviral potential against HCMV in cell-based assays. These studies identified eight analogs of 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes for further characterization, most of which inhibited pUL89-C with single-digit μM IC50 values, and conferred antiviral activity in μM range. TSA and molecular modeling of selected analogs corroborate their binding to pUL89-C. Collectively, our biochemical, antiviral, biophysical and in silico data suggest that 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes can be used for designing inhibitors of HCMV pUL89-C.

Original languageEnglish (US)
Article numbere202200334
JournalChemMedChem
Volume17
Issue number17
DOIs
StatePublished - Sep 5 2022

Bibliographical note

Funding Information:
This research was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, grant number R01AI136982 (to RJG and ZW). We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing molecular modeling resources.

Funding Information:
This research was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, grant number R01AI136982 (to RJG and ZW). We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing molecular modeling resources.

Publisher Copyright:
© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Keywords

  • 8-hydroxy-1,6-naphthyridine-7-carboxamide
  • endonuclease
  • human cytomegalovirus
  • inhibitor
  • pUL89-C

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