TY - JOUR
T1 - Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease
T2 - Synthesis and biological characterization
AU - He, Tianyu
AU - Edwards, Tiffany
AU - Majima, Ryuichi
AU - Jung, Eunkyung
AU - Kankanala, Jayakanth
AU - Xie, Jiashu
AU - Geraghty, Robert J.
AU - Wang, Zhengqiang (ZQ)
N1 - Publisher Copyright:
Copyright © 2022 Elsevier Inc. All rights reserved.
PY - 2022/12
Y1 - 2022/12
N2 - The terminase complex of human cytomegalovirus (HCMV) is required for viral genome packaging and cleavage. Critical to the terminase functions is a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We have previously reported metal-chelating N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human immunodeficiency virus 1 (HIV-1) RNase H. In the current work, we have synthesized new analogs and resynthesized known analogs of two isomeric HtPD subtypes, anti-HtPD (13), and syn-HtPD (14), and characterized them as inhibitors of pUL89-C. Remarkably, the vast majority of analogs strongly inhibited pUL89-C in the biochemical endonuclease assay, with IC50 values in the nM range. In the cell-based antiviral assay, a few analogs inhibited HCMV in low μM concentrations. Selected analogs were further characterized in a biophysical thermal shift assay (TSA) and in silico molecular docking, and the results support pUL89-C as the protein target of these inhibitors. Collectively, the biochemical, antiviral, biophysical, and in silico data reported herein indicate that the isomeric HtPD chemotypes 13–14 can serve as valuable chemical platforms for designing improved inhibitors of HCMV pUL89-C.
AB - The terminase complex of human cytomegalovirus (HCMV) is required for viral genome packaging and cleavage. Critical to the terminase functions is a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We have previously reported metal-chelating N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human immunodeficiency virus 1 (HIV-1) RNase H. In the current work, we have synthesized new analogs and resynthesized known analogs of two isomeric HtPD subtypes, anti-HtPD (13), and syn-HtPD (14), and characterized them as inhibitors of pUL89-C. Remarkably, the vast majority of analogs strongly inhibited pUL89-C in the biochemical endonuclease assay, with IC50 values in the nM range. In the cell-based antiviral assay, a few analogs inhibited HCMV in low μM concentrations. Selected analogs were further characterized in a biophysical thermal shift assay (TSA) and in silico molecular docking, and the results support pUL89-C as the protein target of these inhibitors. Collectively, the biochemical, antiviral, biophysical, and in silico data reported herein indicate that the isomeric HtPD chemotypes 13–14 can serve as valuable chemical platforms for designing improved inhibitors of HCMV pUL89-C.
KW - Endonuclease
KW - Human cytomegalovirus
KW - Inhibitor
KW - N-hydroxy thienopyrimidine-2,4-diones (HtPD)
KW - pUL89-C
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U2 - 10.1016/j.bioorg.2022.106198
DO - 10.1016/j.bioorg.2022.106198
M3 - Article
C2 - 36265353
AN - SCOPUS:85141890426
SN - 0045-2068
VL - 129
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 106198
ER -