TY - JOUR
T1 - 8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease
AU - Jung, Eunkyung
AU - Majima, Ryuichi
AU - Edwards, Tiffany C.
AU - Soto-Acosta, Ruben
AU - Geraghty, Robert J.
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.
PY - 2022/9/5
Y1 - 2022/9/5
N2 - Human cytomegalovirus (HCMV) replication requires a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C) for viral genome packaging and cleavage. We have previously shown that pUL89-C can be pharmacologically inhibited with designed metal-chelating compounds. We report herein the synthesis of a few 8-hydroxy-1,6-naphthyridine subtypes, including 5-chloro (subtype 15), 5-aryl (subtype 16), and 5-amino (subtype 17) variants. Analogs were studied for the inhibition of pUL89-C in a biochemical endonuclease assay, a biophysical thermal shift assay (TSA), in silico molecular docking, and for the antiviral potential against HCMV in cell-based assays. These studies identified eight analogs of 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes for further characterization, most of which inhibited pUL89-C with single-digit μM IC50 values, and conferred antiviral activity in μM range. TSA and molecular modeling of selected analogs corroborate their binding to pUL89-C. Collectively, our biochemical, antiviral, biophysical and in silico data suggest that 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes can be used for designing inhibitors of HCMV pUL89-C.
AB - Human cytomegalovirus (HCMV) replication requires a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C) for viral genome packaging and cleavage. We have previously shown that pUL89-C can be pharmacologically inhibited with designed metal-chelating compounds. We report herein the synthesis of a few 8-hydroxy-1,6-naphthyridine subtypes, including 5-chloro (subtype 15), 5-aryl (subtype 16), and 5-amino (subtype 17) variants. Analogs were studied for the inhibition of pUL89-C in a biochemical endonuclease assay, a biophysical thermal shift assay (TSA), in silico molecular docking, and for the antiviral potential against HCMV in cell-based assays. These studies identified eight analogs of 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes for further characterization, most of which inhibited pUL89-C with single-digit μM IC50 values, and conferred antiviral activity in μM range. TSA and molecular modeling of selected analogs corroborate their binding to pUL89-C. Collectively, our biochemical, antiviral, biophysical and in silico data suggest that 8-hydroxy-1,6-naphthyridine-7-carboxamide subtypes can be used for designing inhibitors of HCMV pUL89-C.
KW - 8-hydroxy-1,6-naphthyridine-7-carboxamide
KW - endonuclease
KW - human cytomegalovirus
KW - inhibitor
KW - pUL89-C
UR - http://www.scopus.com/inward/record.url?scp=85135856438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135856438&partnerID=8YFLogxK
U2 - 10.1002/cmdc.202200334
DO - 10.1002/cmdc.202200334
M3 - Article
C2 - 35879245
AN - SCOPUS:85135856438
SN - 1860-7179
VL - 17
JO - ChemMedChem
JF - ChemMedChem
IS - 17
M1 - e202200334
ER -