Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Human cytomegalovirus (HCMV) infection poses a major health threat to immunocompromised individuals. Until recently, treatment of HCMV infection has relied solely on polymerase inhibitors that have safety and resistance issues. pUL89 provides the enzymatic functions for the HCMV terminase complex in viral DNA packaging and is an attractive target for developing a new class of HCMV drugs. However, inhibitors of the endonuclease activity of the C terminus of pUL89 (pUL89-C) were unknown before our recently characterized hydroxypyridonecarboxylic acid (HPCA) hit 7 r (1-(3-chloro-4-fluorobenzyl)-5-hydroxy-4-oxo-1,4-dihydropyridine-3-carboxylic acid; numbered as 10 k in our previous publication: Y. Wang, L. Mao, J. Kankanala, Z. Wang, R. J. Geraghty, J. Virol. 2017, 91, e02152-16). Herein, we explored the structure–activity relationship (SAR) of the HPCA chemotype mainly with regard to the N1 site through the synthesis of 35 analogues. The SAR studies, along with molecular modeling, identified a possible pharmacophore model minimally consisting of a chelating triad and a hydrophobic phenyl or biphenyl methyl substituent at N1. Lastly, our best compounds consistently inhibited pUL89-C in the low micromolar range in biochemical assays and exhibited strong antiviral activity without cytotoxicity, laying a solid medicinal chemistry foundation for further HCMV drug discovery efforts targeting pUL89-C.

Original languageEnglish (US)
Pages (from-to)1658-1663
Number of pages6
JournalChemMedChem
Volume13
Issue number16
DOIs
StatePublished - Aug 20 2018

Bibliographical note

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • endonucleases
  • human cytomegalovirus
  • hydroxypyridonecarboxylic acids
  • structure–activity relationships
  • terminase complex

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