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

Tianyu He; Tiffany C. Edwards; Jiashu Xie; Hideki Aihara; Robert J. Geraghty; Zhengqiang Wang

doi:10.1021/acs.jmedchem.2c00203

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

Tianyu He, Tiffany C. Edwards, Jiashu Xie, Hideki Aihara, Robert J. Geraghty, Zhengqiang Wang

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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 language	English (US)
Pages (from-to)	5830-5849
Number of pages	20
Journal	Journal of medicinal chemistry
Volume	65
Issue number	7
DOIs	https://doi.org/10.1021/acs.jmedchem.2c00203
State	Published - 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.

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© 2022 American Chemical Society. All rights reserved.

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

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.",

author = "Tianyu He and Edwards, {Tiffany C.} and Jiashu Xie and Hideki Aihara and Geraghty, {Robert J.} and Zhengqiang Wang",

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: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

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language = "English (US)",

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AU - He, Tianyu

AU - Edwards, Tiffany C.

AU - Xie, Jiashu

AU - Aihara, Hideki

AU - Geraghty, Robert J.

AU - Wang, Zhengqiang

N1 - 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.

PY - 2022/4/14

Y1 - 2022/4/14

N2 - 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.

AB - 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.

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

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