4,5-Dihydroxypyrimidine Methyl Carboxylates, Carboxylic Acids, and Carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease

Research output: Contribution to journalArticlepeer-review

Abstract

Human cytomegalovirus (HCMV) terminase complex entails a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We report herein the design, synthesis, and characterization of dihydroxypyrimidine (DHP) acid (14), methyl ester (13), and amide (15) subtypes as inhibitors of HCMV pUL89-C. All analogs synthesized were tested in an endonuclease assay and a thermal shift assay (TSA) and subjected to molecular docking to predict binding affinity. Although analogs inhibiting pUL89-C in the sub-μM range were identified from all three subtypes, acids (14) showed better overall potency, substantially larger thermal shift, and considerably better docking scores than esters (13) and amides (15). In the cell-based antiviral assay, six analogs inhibited HCMV with moderate activities (EC50= 14.4-22.8 μM). The acid subtype (14) showed good in vitro ADME properties, except for poor permeability. Overall, our data support the DHP acid subtype (14) as a valuable scaffold for developing antivirals targeting HCMV pUL89-C.

Original languageEnglish (US)
Pages (from-to)5830-5849
Number of pages20
JournalJournal of medicinal chemistry
Volume65
Issue number7
DOIs
StatePublished - Apr 14 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 R.J.G. and Z.W.), and the National Institute of General Medical Sciences, the National Institutes of Health, grant number R35GM118047 (to H.A.). We thank the Minnesota Supercomputing Institute for molecular modeling resources. The preparation of the structure data file (SDF) for molecular docking used JChem for Office licensed by ChemAxon.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of '4,5-Dihydroxypyrimidine Methyl Carboxylates, Carboxylic Acids, and Carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease'. Together they form a unique fingerprint.

Cite this