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.
Bibliographical noteFunding 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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